Fonseca Discusses the Importance of MRD Negativity in Patients With High-Risk Multiple Myeloma

Rafael Fonseca, MD, recently shared the treatment considerations and decisions he makes when treating patients with multiple myeloma. Fonseca, professor of medicine, chair, Department of Internal Medicine, Mayo Clinic, explained how he would treat these patients based on case scenarios during a <em>Targeted Oncology </em>live case-based peer perspectives presentation.

Rafael Fonseca, MD

Rafael Fonseca, MD, recently shared the treatment considerations and decisions he makes when treating patients with multiple myeloma. Fonseca, professor of medicine, chair, Department of Internal Medicine, Mayo Clinic, explained how he would treat these patients based on case scenarios during aTargeted Oncologylive case-based peer perspectives presentation.

Case 1

December 2013

A 77-year-old African American man received a diagnosis of stage III multiple myeloma 24 months ago and was not eligible for transplant based on his level of frailty. His cytogenetics showed hyperdiploid disease.

He received treatment with lenalidomide (Revlimid) at 15 mg daily and low-dose dexamethasone. After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL; therapy was continued.

December 2015

His laboratory findings showed:Hemoglobin levels, 11.4 g/dL; creatine clearance, 1.0 mg/dL. Additionally, his M-protein rose from 0.6 g/dL to 1.2 g/dL to 1.5 g/dL. He reported feeling tired, but continued to do well functionally.

TARGETED ONCOLOGY: What are your general impressions of this patient?

Our first case is a typical situation, where you have an individual who was recently diagnosed with myeloma. Part of what we are trying to do [in these types of patients] is address the importance of looking at the specific details regarding the clinical picture [and] the biology of the disease. In this case, we have a patient who has hyperdiploid disease, which tends to be more common in elderly patients. It is an important factor, because we now know that high-risk myeloma tends to have a slight preference for younger patients.

Do you continue the patient on lenalidomide or switch to another therapy?

In this case, the patient was started on lenalidomide and low-dose dexamethasone. For the most part, the patient does well, until a couple of years later when the patient starts to experience relapse. There [are] a lot of questions that clinicians have, where we think: If we have a patient on low-dose maintenance, as is the case here with this patient, what is the value of increasing the dose? Or should we switch to another therapy? Part of this is unanswered.

We know anecdotally that some people will respond to higher doses of the same medication. And there is also significant potential, but it is probably more common that the increase will not do the job. At this point, you would have to think about different agents. This is important in a population where the logistics of treatment are of high value. Ideally, we will have situations where you can actually get biomarkers that would allow us to predict whether or not something will work.

His lenalidomide was increased to 25 mg daily by the local physician.

May 2016

The patient was hospitalized 2 months previously for pneumonia and complained of increasing back pain, fatigue, and weakness. His laboratory findings showed: M-protein, 2.1 g/dL; serum beta-2 microglobulin, 6.2 mg/L; albumin, 2.1 g/dL; creatinine clearance, 32 ml/min.

His skeletal survey showed new compression fracture in the L4/L5 vertebrae. A bone marrow biopsy showed 30% involvement by abnormal appearing plasma cells, confirmed by CD138+ immunohistochemistry stain. He had an ECOG performance status of 2.

What are the options for this patient when symptomatic disease progression occurs?

We walk through these hypothetical scenarios where the patient has a medication increase. However, there is still progressive disease and clearly the patient will need a change of therapy. What is really interesting is how do we choose therapy for those who have a better-risk disease and are of a more advanced age. So, we want to focus on all of the alternatives that a patient like this has.

It is fair to say that the majority of physicians will think about combination strategies. One of the options regarding combinations would be a proteasome inhibitor in the form of bortezomib (Velcade) or, perhaps, carfilzomib (Kyprolis), both of which could be effectively used in the elderly. We could also consider combinations that would include daratumumab (Darzalex) for this patient, assuming that we have reached a point now where the disease has progressed to such a level where more intense therapy is needed.

In this particular case, because the patient is already on an immunomodulatory drug (IMiD), the patient goes on to get treated with what we call a CASTOR-like regimen. So, this was the combination of daratumumab with bortezomib and dexamethasone. However, other options could also be daratumumab and another IMiD, such as pomalidomide (Pomalyst) or, just as well, the combination with carfilzomib. So, there are a lot of questions, and I think one of the challenges that doctors now face is: How do you position the various drugs in combination and in what sequence? It would be great to have all of the answers, but I think the interactive cases that we have highlight the multiple choices for patients.

For this patient, I would do 1 of 2 things. This person could be treated with a combination of daratumumab, but I would use pomalidomide. Or a combination of carfilzomib and pomalidomide would be appropriate. I would make sure that we do the proper dose adjustment for dexamethasone, as well as any chemotherapy agents to make sure the dose of the therapy we are going to use for someone in their late 70s is consistent with acceptable toxicity and tolerability of the patient.

The patient was treated with daratumumab, weekly subcutaneous bortezomib, and dexamethasone.

What supportive care measures are necessary for this patient?

As far as supportive care for this patient, there are several things that need to be looked at in greater detail. I have already discussed the toxicity and the appropriate doses for the medication. This is a patient who will also need support with growth factors. We should be careful with this in the case of myeloma. This patient will most likely have significant biosuppression associated with the chemotherapy drugs.

IMiDs, particularly with advancing age or in combination, for instance, can cause substantial neutropenia, where we actually use lower doses of lenalidomide to start this combination. This is usually 2 mg, perhaps even 2 mg every other day, for a patient of this particular age. This patient developed a recompression fracture, so the use of bone-protecting agents would be appropriate. In this case, the patient had a creatinine clearance of 32 mL/min, so the use of a monoclonal antibody, denosumab (Xgeva), would also be an appropriate option. Also, one must not forget, for selective patients with myeloma, the use of vertigo-augmentation procedures, such as vertebroplasty or kyphoplasty.

Case 2

July 2011

A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma. Her genetic testing showed translocation 14;16.

At the time, she was treated with lenalidomide, bortezomib, and dexamethasone (RVD) induction therapy, followed by autologous stem cell transplant. She achieved a complete remission with RVD and transplant and was placed on lenalidomide maintenance therapy.

What are your general impressions of this case?

This is a case of a patient who is younger, she's in her early 60s, who has newly diagnosed high-risk multiple myeloma. This situation of high risk remains important for a number of reasons. The counseling for patients is standard according to the risk classification. [Although] much progress has been made in the treatment of myeloma, for those patients who have high-risk disease, there are significant challenges. Recent survival data show we still have a significant drop in our survival curves.

This is a patient who should be considered, unless proven otherwise, for stem cell transplant. Proper positioning of therapy becomes important as we think about maximizing the duration of a deep response, hopefully a complete response, and also with minimal residual disease (MRD) negativity. In particular, this patient has a translocation of 14;16. It is important to remember that high-risk markers include 14;16 or 4;14 and deletion 17p. There are new ways, and I would argue even better ways, of determining high risk. Although, they do not all have the penetration within the clinical practice. This would include things such as gene-expression profiling and, most recently, the use of next-generation sequencing (NGS) in the hopes of finding specific mutations. But with what we know, 14;16 should be considered in the high-risk category for patients. This is not 100% determinant. We have patients who have high-risk markers who do very well in the long term, including patients in my practice.

What is the rationale for the choice of up-front therapy in this patient?

This patient was treated with a combination of lenalidomide, bortezomib, and dexamethasone by stem cell transplant. For a patient with high-risk disease, there are 2 questions that become critically important for up-front therapy: What is the best regimen? I think this can be described in the following way: For patients who have high-risk myeloma, our approach philosophically would need to be similar to what we are using for patients with acute leukemia. Our control strategy would be insufficient. In fact, Mayo Clinic has included in its start-of-treatment guidelines a consideration of use for the combination of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) for high-risk patients.

The next question, which we don't go into in this particular case, is the addition of monoclonal antibodies to frontline therapy, something that is being excessively tested in clinical trials. We have considered, for patients who are of high-risk disease, the combination of KRd. This seems to be a better regimen for this patient population. We say so with the knowledge that there will be a transplant in the backhand for this induction therapy held by appropriate maintenance strategies. This is a young patient and [she is] able to go through the transplant, and we think that the best induction therapy is very important.

Which patients are typically candidates for maintenance therapy?

For patients who have high-risk disease, there are a number of clinical trials that are showing an increased survival with the use of a proteasome inhibitor added to the stem cell transplant. This concept is limited to proteasome inhibitors right now only because we don't have the data with monoclonals, such as daratumumab. What we know is that patients who receive proteasome inhibitors in the posttransplant setting who have high-risk markers appear to do better than those who do not. There [are] a lot of data published with regard to long-term experience with the use of bortezomib plus stem cell transplant for patients with high-risk disease.

By circulation, we do this with high-risk markers. So, this has been mostly tested on 14 and deletion 17p. But I would argue that, for someone who has a 14;16 translocation, we should apply the same principles. In practice, we use either combinations of bortezomib and lenalidomide. We don't exclude IMiDs from these combinations. Or, more frequently, in order to give patients more freedom from the treatment center, we have also used the combination of ixazomib (Ninlaro) and lenalidomide in the maintenance setting. We have optimal induction with best regimens, transplant, and then maintenance that includes a proteasome inhibitor. So those are the big therapeutic considerations from the physician’s perspective.

How do you measure progress and what duration do you recommend?

This is where the considerations for the determination for MRD comes into play. I would argue that for this patient population, it is particularly important to achieve MRD negativity. In fact, I have a personal case with an individual who had a translocation of deletion 17p who was treated with stem cell transplant and started maintenance therapy with the RVD combination, and later switched to ixazomib, lenalidomide, and dexamethasone. Two years out, we did a bone marrow, which was MRD negative. Three years out, we did another, which was MRD negative with a sensitivity of 10-6using NGS. The question was posed by the patient and the family members: What do we do from this point on? After extensive discussion, we decided to stop maintenance therapy at that point. That is the beauty of how we are getting to the point where we can have deep control of high-risk disease, hopefully so that the patient will continue to do much better in the long-term.

What is the potential impact of these data?

There are multiple ways in which people are measuring MRD negativity. [One way is through the] process of NGS. However, flow cytometry has been promulgated as something that can be done, as well, to measure MRD negatively. Most recently, they proposed that they could take it to similar levels of sensitivity as NGS.

This construction of the case needs to be put in context of the broader perspective of what is happening to myeloma prognosis. We published this study last January in the journal ofLeukemia, which looked at the survival of patients with myeloma over time.1The reason I show this study, first of all is because this is a very powerful study with close to 10,000 patients. We use real-world data, so we use time of diagnosis based onICD9(International Classification of Diseases, Ninth Revision)andICD10codes and cross reference this. As time goes by, we [segregate] patients on their year of diagnosis. The more recent diagnoses were associated with a longer survival. We contrast this with patients in the top curves. Our patients and the majority of patients are in the same database. And secondly, you see there is a much sharper slope of the curve downwards, which we think represents patients who have high-risk disease.

I already alluded to MRD and the importance of it in measuring residual disease. A recent study of a Spanish group has shown that MRD negativity may be the goal, and perhaps the only goal.2What they did is they broke down patients who had different levels of response and they looked specifically at those who had a complete response. They decided to break the complete response to either complete response MRD positive versus those [who] are complete response MRD negative. What they found is that if you have a complete response and are MRD positive, your outcomes are similar to any other level of response, including partial response or complete response. On the other hand, if you have a complete response and have MRD negativity, then the outcomes are far superior. This tells us that all of this effort in classifying the responses of myeloma end up just an academic exercise. At the end of the day, getting very deep responses is what matters.

Are these results strong enough to potentially replace transplant in transplant-eligible patients?

There is a recent study that I used for reference, which is a French study from 2009 that looks at the combination of RVD followed by transplant and then more RVD versus RVD alone.3This was a trial to test whether transplant could be omitted in the treatment of patients with myeloma. The spoiler alert, it [can’t] yet. I think we still see that transplant provides benefit. But part of this has to do with the response rate that you get with transplant. Today, specifically, this has to do with the status of MRD negativity, which is higher in patients who go through transplant.

The other side of that coin is that if a patient is able to achieve MRD negativity, whether it is with or without transplant, then the outcomes appear to be similar. The logical next question is: What if you measure MRD negativity before you do the transplant, and is there any benefit? Of course, this needs to be tested respectively. Until then, I have had a patient [who] came to me with this very specific graph that compares the RVD versus the transplant arm and told me that they did not want to go through transplant, and instead, they wanted MRD testing in their bone marrow. We decided to go ahead with the bone marrow test for MRD negativity. This is a patient who had been treated with RVD, just like in the French study. And low and behold, the MRD was positive, but only in 1 cell in a million. Of course, the patient already decided that he was not interested in transplant. So, we decided not to proceed with it and to continue with RVD. Fortunately, he is doing very well. This is the kind of level of sophistication that we are seeing in this field.

August 2016

On routine follow-up, the patient reported having mild fatigue, but continued to work full time; she had grade 1 neuropathy. Her laboratory findings showed: M-protein: 1.4 g/dL; light chain levels continue to rise; hemoglobin, 10.3 g/dL; creatinine clearance, 1.3 mg/dL.

How would you define progression in myeloma?

I think the goals of therapy can be seen in 2 ways. When you have the first relapse, you want to be as aggressive against the disease as possible. And you want to set your strategy so that you can reduce the myeloma burden to the lowest level possible.

But what happens when the patient starts progressing? When a patient is faced with their first relapse, that progression needs to be taken very seriously. But one of the things that is still not fully defined is: When do we actually pull the trigger to start treatment again? I think the extremes are obvious. If someone has a slow clinical relapse, treatment is indicated and no one would question that. When it is less defined is with a so-called biochemical relapse. We only consider biochemical relapses when there are genetics that indicate clonal progression.

I recently addressed this situation on my social media account. I asked myeloma doctors: When do you start therapy? Just when the protein reappears—this can be a minimal rise in the free light chain—or do you do so only when that reappears and there are changes upward? I think the majority of people want to see some increased levels of the protein because we all recognize that we have patients in our practice [who] can have a very small amount of residual protein but they don't necessarily progress immediately. While there are also some individuals [who] would make the argument for the very first relapse, particularly for patients who did well with the first-line therapy and had a long period disease control, [they] should maybe go hard again. So, there is an unresolved philosophical difference on how we approach this. I think most people are looking at a rise in the serum concentration of the free light chain, or the M spike, with the genetics of that being important [for deciding when] to start the next line of therapy,

What are the options for treatment of a patient who is largely asymptomatic with good performance status but who is developing biochemical relapse on lenalidomide?

One of the key questions for the myeloma community right now is: What do you recommend for that patient who progresses on lenalidomide maintenance? It has become clear that maintenance with lenalidomide does provide significant benefit when it comes on to progression-free survival and overall survival.

That takes us to the question: Is there any benefit of increasing doses? Potentially, but most people do not think that is the case. So, we tend to think of the treatment of this patient in a couple of ways: (1) What are the genetics of how rapid it is happening? (2) How aggressive is the relapse? Most people believe that if you have an aggressive relapse, we need to do 1 of 2 things. You either need to embark on a daratumumab-based combination, and a study suggests that empirically this can be used with the same drug of lenalidomide, but also that we would switch pomalidomide for that combination in case there is a possibility of overcoming that lenalidomide-associated resistance with that combination. Of course, that is one approach. The other approach is the carfilzomib-based combination. I think those 2 options are clearly the perfected options for a patient with more aggressive forms of relapse.

If a patient had a somewhat indolent relapse, there are other considerations. If this was potentially someone who is living away from the treatment center, who would have logistic complications with getting the infusions, we would consider an old regimen. Probably our choice would be the combination of ixazomib, pomalidomide, and dexamethasone, which has been used somewhat empirically, but with good success. For select patients, one might also consider the combination of elotuzumab (Empliciti) with IMiDs in this patient population. These 2 last combinations are probably geared toward those that have more indolent relapse. We do not know the best approach because they haven’t been tested head to head. However, the heterogeneity of myeloma biology, and the heterogeneity of the clinical features of progression, dictate by necessity that some of this is implemented in a somewhat empirical fashion. Now, I’ll be the first one to say this, there is a possibility that there are better ways in which we can sequence these drugs, which many myeloma doctors are currently thinking about.


  1. Fonseca R, Abouzaid S, Bonafede M, et al. Trends in overall survival and costs of multiple myeloma, 2000-2014.Leukemia. 2014;31(9):1915-192 doi: 10.1038/leu.2016.380.
  2. Lahuerta JJ, Paiva B, Vidriales MD, et al;GEM (Grupo Espa&ntilde;ol de Mieloma)/PETHEMA (Programa para el Estudio de la Terap&eacute;utica en Hemopat&iacute;as Malignas) Cooperative Study Group. Depth of response in multiple myeloma: a pooled analysis of 3 PETHEMA/GEM clinical trials.J Clin Oncol. 2017;35(25):2900-2910. doi: 10.1200/JCO.2016.69.2517.
  3. Attal M, Lauwers-Cances V, Hullin C, et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the intergroupe Francophone Du Myelome (IFM/DFCI 2009 trial).Blood. 2015;126:391. Accessed May 21, 2018.