Up-front Therapy Options in Multiple Myeloma, Including the Role of Transplant

Paul G. Richardson, MD:This case is a description of a very lovely 61-year-old lady who was diagnosed originally with stage II myeloma in July of 2011. At the time of her assessment, she was found to have high-risk cytogenetics as reflected by translocation 4:16 on florescent and CT hybridization. Very appropriately, her initial treatment was RVD (lenalidomide, bortezomib, dexamethasone). This was then followed by autologous stem cell transplant after achieving partial response to induction. She remained in sustained remission, and based upon her clinical presentation, including her cytogenetics, lenalidomide maintenance was used. Again, very appropriately.

Now, this ensured a 5-year progression-free interval as a result of her maintenance, and then subsequently she has relapsed. Now, in the context of her relapse, I think the pertinent positive here is that she has clear biochemical progression. She does have some light chain production, which is resulting in some renal dysfunction, and in that context, she clearly needs therapy. She enjoys excellent performance status, and she’s working full time, so our choice of therapy needs to be framed around that.

Now, when we think of her treatment, it is reasonable to discuss a little bit around the rationale for her initial treatment. RVD-based therapy for the initial treatment of myeloma in younger patients has become now a standard of care. This was originally based on the observation preclinically that lenalidomide and bortezomib in preclinical models of myeloma were synergistic in its activity. This, in turn, informed the clinical trial in the relapsed-refractory setting, in which impressive activity was seen, even in patients in whom prior immunomodulatory and proteasome inhibitor-based therapy had been used. So, the fact that they had previous lenalidomide or previous bortezomib did not preclude them from responding to the combination. In fact, we were very encouraged by not only the response rate, but the excellent tolerability and, moreover, the median overall survival and progression-free survival from this initial phase I and II experienced in the relapsed-refractory setting.

This, in turn, informed a series of studies and, most importantly, the up-front study of RVD conducted in 66 patients in a multicenter setting in which we demonstrated that 100% of patients enjoyed PR or better. And in the phase II cohort of that trial, we demonstrated that 52% of patients achieved complete remission or near-complete remission to this initial treatment approach. So, therefore, the use of RVD in this patient is a very rational choice. The tolerability of the approach is also generally very good, particularly with the use now of subcutaneous bortezomib, which reduces the neurotoxicity of the bortezomib and, at the same time, preserves efficacy.

So, the use of RVD for this particular patient is an induction strategy and was really very appropriate. It’s important to note also that the timing of transplantation now has become a very key question, because in younger transplant-eligible patients, it’s very reasonable now to think about keeping transplant relatively in reserve because what we’ve shown so far in prospective randomized trials is that whilst there is a progression-free survival benefit to early transplant, there’s no overall survival benefit, and therefore, patients can legitimately have the choice of keeping their transplant in reserve if needs be.

In any event, in this particular case, this woman underwent autologous stem cell transplant. She enjoyed a partial response to therapy, which is important. So, she got initial partial response to RVD. She then got continued partial response from her transplant and then, very appropriately, went onto maintenance treatment.

As we think about the role of transplant for the up-front treatment of myeloma, I think it’s important to recognize that the treatment paradigm is changing, that we have the ability to collect and store stem cells and, therefore, keep transplant in reserve for selected patients. I think it’s important, though, to recognize that in younger patients, obviously, autologous stem cell transplant remains a standard of care. However, one size does not fit all, and what’s very clear is that we can reasonably keep in a subset of patients’ transplant in reserve and use it later in their course. Now, this particularly matches for a variety of reasons.

First and foremost, many patients don’t wish to go straight to transplant immediately after diagnosis—for a variety of reasons. And second of all, as patients are living much, much longer with their illness, we have to take into account not only the acute toxicities of transplantation, but also recognize the late ones that we obviously have to be aware of as patients live longer. Most important in that category are the myelodysplastic syndromes that we do see post-transplant. Fortunately, these are rare, but what we recognize, though, is that they do appear to increase over time. And so, in that context, it’s very reasonable to bear these considerations in mind when counseling a patient about the role of transplant.

Obviously, it can enhance response and improve progression-free survival. We know that from randomized trials. What’s very interesting from current randomized trials, however, is that there’s no difference in overall survival. In other words, in transplant later versus early, there is no impact on the overall survival of the patient. That’s very important information, and what we’re recognizing is that maintenance really matters. Because of that, it also changes the equation of where we think transplant may belong, recognizing that after initial treatment, some form of maintenance is certainly required. The question is, do you need a transplant with everyone? Certainly, in my own practice outside of clinical trials, that’s very much a discussion with patients, what their particular lifestyle choices may be, and, very importantly, also how they do with their initial treatment.

For example, if a patient has an excellent response to RVD therapy, tolerates it very well, achieves complete remission, it’s very reasonable to collect and store bone marrow and allow them to wait on some form of maintenance. Then, at the first relapse, appropriately salvage with highly-effective regimens and transplant. In another patient in whom the initial treatment effect is less optimal, they don’t achieve a very high quality response. They struggle with the initial treatments in some way, although that’s not common, but certainly well recognized. That may be someone in whom transplantation may really add to the therapeutic benefit of the initial approach.

Case Scenario 1:

July 2011

• The patient is a 61-year-old Caucasian female who was diagnosed with stage II MM. Genetic testing showed her to have t(4:16). At the time she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy followed by autologous stem cell transplantation.
• She achieved a partial response with RVD and remained in remission. Based on her high-risk cytogenetics, the patient was placed on lenalidomide maintenance therapy.

August 2016

• Routine follow up shows that her M-protein levels have now risen to 1.4 g/dL and her light chain levels continue to rise.
• Although she has developed mild anemia and her creatinine level is slightly elevated to 1.3 mg/dL, she continues to work full-time, has no bone pain, and a has a normal calcium level.