We have a 75-year-old gentleman who was diagnosed with multiple myeloma. He originally got treatment with lenalidomide and dexamethasone for about 9 months and then, due to his own preference, stopped therapy. Generally, these days we try to give therapy until progression. But in this case, the gentleman desired to stop treatment. The good thing is that he had a very good partial response, and he after that went a number of years without any need for therapy. He once again started showing evidence of some fatigue and some constitutional symptoms. Thereafter, a workup showed that his disease was starting to progress with some mild anemia and back pain, with new compression fractures. So this is a situation where we know that a patient is going to probably require treatment. He underwent a bone marrow biopsy again, and as expected demonstrated a number of plasma cells in excess of normal. Therefore, he also had chromosomal testing done, and that showed that he had this adverse 17p deletion abnormality.

The treatment for multiple myeloma has certainly evolved, both for the transplant-eligible and for the transplant-ineligible patients. For transplant-ineligible patients, we&rsquo;ve certainly come a long way from the era when we used to give these patients melphalan and prednisone. We went through a period where people tried to improve upon the melphalan/prednisone standard by adding a third drug. Melphalan/prednisone/thalidomide, melphalan/prednisone/Revlimid, and melphalan/prednisone/Velcade have all shown benefit over melphalan and prednisone. But it was always felt that melphalan was a drug that if we could do away with it, would be best, given its unpredictable response, somewhat delayed response, and its toxicity.

The trial that was done a few years ago was called the FIRST trial, where lenalidomide and dexamethasone was compared to a standard of melphalan/prednisone/thalidomide, and continuous therapy with lenalidomide and dexamethasone until progression proved to be superior. It led to a new standard being established for transplant-ineligible patients. Since that time, there have certainly been other studies that have been done and reported on. We know that in patients who are named transplant-ineligible but are still in reasonably good shape for treatment, often we will give them a 3-drug regimen. One of the more popular ones is the 3-drug regimen of bortezomib with lenalidomide and dexamethasone [VRd].

The fact is, the 3-drug regimen at full intensity often is not well tolerated by an elderly population, so the regimen that we call VRd-lite has become popular. You end up giving the Velcade once a week instead of twice a week, the lenalidomide at a lower dose, as the dexamethasone. For patients who are between 70 and 80 years of age, that has become a popular regimen in recent years. For people who are octogenarians, for whom we are a little hesitant to give 3 drugs, lenalidomide and dexamethasone is still a standard that people accept.

Now, more recently, we&rsquo;ve had data emerge from a new generation of trials looking at monoclonal antibodies in frontline therapy. In that regard, daratumumab with melphalan, Velcade, and Decadron was shown to be superior to the FDA-approved standard of Velcade with melphalan and prednisone. And what we now know is that it is the first quad, as we call it, the first 4-drug regimen that we have FDA approved for myeloma. There has been some hesitancy in adopting that widely, given that there is melphalan in the mix, and people have wanted to move away from melphalan. We also know from the American Society of Hematology meeting in December 2018, we had a presentation that showed that the 3-drug regimen of daratumumab with Revlimid and Decadron was superior to the 2-drug regimen of Revlimid and Decadron. So I think that once that gets approved by the FDA in the future, that will become a very popular regimen for the transplant-ineligible patient population.

There are a number of other trials ongoing that will also be reported on in the near future that are eagerly awaited. These include trials looking at ixazomib with lenalidomide and dexamethasone compared to lenalidomide and dexamethasone, and a trial of elotuzumab with lenalidomide and dexamethasone, again compared to lenalidomide and dexamethasone. How these fit into the landscape, once these trials hopefully are positive and lead to the approval of these drugs, remains to be seen.

Impressions of an Elderly Male With R/R Multiple Myeloma

Treatment for relapsed/refractory [R/R] myeloma has evolved tremendously over the last several years. We now have a number of 3-drug regimens that we use in the relapsed/refractory space. Until a few years ago, it was fairly common to use 2-drug regimens at relapse. And I think that the shift to 3-drug regimens has been driven by a number of studies that have shown improved progression-free survival, and some have even shown an improved overall survival when you use a 3-drug regimen instead of a 2-drug regimen in patients with relapsed/refractory disease. So the prevailing 2-drug regimens used to be, once again, lenalidomide and dexamethasone, and bortezomib and dexamethasone. But now we would rarely give 2-drug regimens to patients unless there&rsquo;s a fear of toxicity.

The 3-drug regimens that have become popular in the recent several years include Kyprolis with lenalidomide and dexamethasone, daratumumab with lenalidomide and dexamethasone, elotuzumab with lenalidomide and dexamethasone, and ixazomib with lenalidomide and dexamethasone. Also, the FDA recently approved a 3-drug regimen of pomalidomide with Velcade and Decadron. So there is no deficiency of regimens that we can turn to.

I think that the choice of a regimen has to be individualized to a patient&rsquo;s situation. There is no single accepted standard of care that has evolved. Even within a physician&rsquo;s practice, one chooses a regimen based on a particular patient&rsquo;s desires and needs, to some extent. In that regard, in the patient that we have discussed here, the 75-year-old gentleman, often patients like this desire an all oral regimen. They desire, if possible, not to have to come to the doctor&rsquo;s office to have an infusion of a drug every week. So in this patient, the choice of ixazomib/lenalidomide/dexamethasone was appropriate given the patient had a desire to take something that was oral.

What is also important to note is that in a patient with a 17p deletion, trials have shown that the 3-drug regimen of ixazomib/lenalidomide/dexamethasone does as well for patients who have the 17p deletion as for those who do not. And so, I think that this patient, treated with ixazomib/lenalidomide/dexamethasone, was able to maintain a quality of life that could have been disrupted by repeated physician visits. I will say that in the future, patients will always move on to the alternative. So if this patient has received ixazomib/lenalidomide/dexamethasone in second-line therapy, and we are hoping that his ability to tolerate treatment persists even beyond, people will certainly move on to one of the other 3-drug regimens that we just discussed.

Patients who are older and who are not transplant-eligible certainly have benefited from the advent of modern therapies. Their benefit may not be as marked as for the transplant-eligible population. In the transplant-eligible population, we will often be comfortable quoting median survivals approaching 10 years. I think for the transplant-ineligible patients, it&rsquo;s often probably somewhere between 5 and 7 years, but that is still a dramatic improvement over what we were achieving just a decade and a half ago when median survivals of 3 years or so were often quoted. For patients who are able to tolerate these new drugs, I think they certainly are contributing tremendously to their improvement in outcomes.

Progress in the Treatment of R/R Multiple Myeloma

Patients who are older certainly have more challenging circumstances in terms of deciding on choice of treatment. We have discussed that 3-drug regimens have become the norm. The fact, however, is that for some people we need to improvise treatments because they cannot tolerate 3-drug regimens. In that regard, we know that giving these patients sometimes just a 2-drug regimen of ixazomib and dexamethasone may be sufficient to produce a response and maintain quality of life. In other cases, we sometimes use single agents like daratumumab as well. In this patient with a performance status of 2, the 3-drug regimen seemed to be an appropriate initial choice. It would, I think, provide the right balance in terms of improving efficacy, depth of response, and progression-free survival, while still maintaining quality of life.

Ixazomib is a drug that adds little to the toxicity of lenalidomide and dexamethasone. It is a drug that certainly has some potential to cause neuropathy and rashes. Like any drug we use for myeloma, some element of fatigue is often reported. It doesn&rsquo;t add much to the hematological toxicity of lenalidomide and dexamethasone. So I think that in an older population, this 3-drug regimen of ixazomib/lenalidomide/dexamethasone is not much more toxic than what you would usually expect with lenalidomide and dexamethasone.

The choice of treatment for patients with relapsed/refractory [R/R] disease is one that requires taking into account a number of factors, which include patient-related factors, disease-related factors, and things of the nature of the social environment of a patient. Patient-related factors, in addition to the age, include their comorbidities, their performance status, and their renal function. For disease-related factors, the aggressiveness of the disease and the cytogenetics of the tumor play a role in our decision making. And then, does the patient have a caregiver? How far away does the patient live? What is the patient&rsquo;s own desire? Is he able to afford co-pays for oral medicines?

These all factor into our choice of treatment. The patients who are being followed closely by doctors, especially when they&rsquo;re seeking a second-line option are often picked up when the disease is just showing evidence of what we call a biochemical progression. They&rsquo;re often not symptomatic. And in that scenario, it is often debated whether changing treatment is even necessary. However, with the abundance of options that we have now, we certainly have probably started treating patients earlier than we would have in the past.

The things that we often do at the time of first relapse in a patient who has otherwise a biochemical progression is to get a PET [positron emission tomography] scan and a bone marrow biopsy, to see if we can get a better sense of the bulk of disease. In a patient who has biochemical progression and has a PET scan, I personally treat that patient as if he or she has true symptomatic progression with the evolution of new CRAB [calcium elevated, renal failure, anemia, bone lesions] criteria that the audience is familiar with here, in terms of its relationship to multiple myeloma.

For patients who have slow progression of their disease, I&rsquo;m often comfortable using a 3-drug regimen like elotuzumab/Revlimid/Decadron or ixazomib/lenalidomide/dexamethasone. And these regimens are usually well tolerated. They provide a good balance between toxicity and efficacy. Also, convenience favors oral regimens.

So the regimen of elotuzumab/lenalidomide/dexamethasone, though a regimen that includes an IV [intravenous] drug, is usually well tolerated. And again, for patients with biochemical progression, the regimen offers a good choice. In patients who have more rapid progression of their disease, who are more symptomatic and otherwise healthy, I think that often we use 3-drug regimens like daratumumab with either lenalidomide or pomalidomide and dexamethasone, sometimes pairing the daratumumab with bortezomib and dexamethasone. The patients who have gotten daratumumab, or in some cases, even before daratumumab is used, the use of a Kyprolis-based 3-drug regimen is also an option. In that regard, once again, Kyprolis with lenalidomide/dexamethasone, pomalidomide and dexamethasone, or Cytoxan and dexamethasone, for that matter, are popular regimens.

Selecting a Treatment Regimen in R/R Multiple Myeloma

The fact is that patients who have high-risk features seem to have a better outcome when a proteasome inhibitor is used as part of their treatment. And in that regard, patients who have a (4;14) translocation, or 17p deletion especially, there are data that suggest the use of a proteasome inhibitor in combination improves progression-free survival. So that is one thing we keep in mind when we decide on a long-term strategy for patients with high-risk disease.

For patients who have symptomatic, aggressive relapse, we do certainly use 3-drug regimens over 2-drug regimens unless a patient has a performance status that does not permit us to deliver a 3-drug regimen. Regimens employing daratumumab and Kyprolis are the popular 3-drug regimens that people have used in recent years. Depending on what they have had in their prior line of therapy, there are a number of 3-drug regimens that can be employed, and daratumumab can be paired with pomalidomide, lenalidomide, or bortezomib. Likewise, Kyprolis can be paired with Revlimid, Cytoxan, or pomalidomide as well. These are popular regimens that are used depending on the given situation.

In regard to ixazomib, lenalidomide, and dexamethasone, that is a regimen that is now FDA approved for the treatment of patients with relapsed and refractory multiple myeloma. The use of ixazomib has been shown to improve progression-free survival and depth of response compared with lenalidomide and dexamethasone alone. Also, with the use of ixazomib, it has been shown that patients have deeper responses the longer they are on therapy. Ixazomib is a convenient once-a-week drug that is well tolerated. It has few adverse effects. Some patients complain of neuropathy. Some patients have some GI [gastrointestinal] intolerance to the drug. It is rare to cause rashes. Generally, the 3-drug regimen of ixazomib, lenalidomide, and dexamethasone is not much more toxic than lenalidomide and dexamethasone alone.

So the 3-drug regimen does offer benefit for patients who desire an oral treatment. Not only in patients who are older where transportation may be an issue, but even in patients who are young and are employed, it is very disruptive to their schedule often to have to take off work to come to a doctor&rsquo;s office to get treatment. And I think in that scenario, the 3-drug regimen of ixazomib, lenalidomide, and dexamethasone, again, offers a convenient option.

Because proteasome inhibitors are thought to be the treatment of choice for patients with high-risk disease, such as those who have a translocation (4;14) or deletion 17p, the oral regimen of ixazomib, lenalidomide, and dexamethasone certainly offers an attractive proposition as well.

Proteasome Inhibitors in High-Risk Multiple Myeloma

The TOURMALINE-MM1 study looked at patients who had relapsed after 1 or more lines of treatment. These patients were randomized to either the 3-drug oral regimen of ixazomib, lenalidomide, and dexamethasone or the prevailing standard at that time of lenalidomide and dexamethasone. The study showed a statistically significant improvement in progression-free survival, which was the primary endpoint of this study. It also showed that patients had deeper responses when ixazomib was added to the 2-drug regimen. The toxicity profile of the 3-drug regimen did not seem to be too different compared to the 2-drug regimen. Also, in the study it was found that high-risk cytogenetic patients, even those with a 17p deletion, seemed to benefit with the addition of ixazomib to lenalidomide and dexamethasone. So this FDA-approved regimen offers a potential convenient effective therapy for a lot of our patients.

The patient that we are talking about today is an older gentleman who has performance status of 2. This gentleman is in need of treatment, and I think that the regimen of ixazomib, lenalidomide, and dexamethasone is very appropriate for a patient of this nature because of the convenience that the regimen offers. It is a regimen that the patient can take at home. The regimen is well tolerated by older individuals. It is a regimen that also, given his 17p deletion, would at least based on the TOURMALINE-MM1 study be effective as well as if he did not have high-risk chromosomal features.

Ixazomib is a drug that I think is appropriate for patients who are older, especially for those who have a limited performance status. The drug&rsquo;s toxicities are relatively mild and the drug is well tolerated. In somewhat frailer patients, one of the things we often try to balance with efficacy is the lack of toxicity. Ixazomib can cause, in some patients, fatigue, but usually it is not too marked. It also in some cases causes the patients to develop a mild neuropathy or a rash, but those are also, in my own experience, not major issues. So, in older patients, I think this drug regimen is well tolerated.

The use of ixazomib also offers older patients an all oral regimen in combination with lenalidomide and dexamethasone. These patients often have issues coming to the doctor&rsquo;s office, so taking a pill at home once a week together with the lenalidomide and dexamethasone offers them the convenience of home administration of the drugs. It is also less disruptive often to the caregivers. They don&rsquo;t have to take off work to bring their loved ones to the doctor&rsquo;s office either. So I think that the 3-drug regimen of ixazomib, lenalidomide, and dexamethasone has advantages that certainly, for a patient who is older and somewhat frailer, go beyond just the patient description and the demographic to extend to his caregivers and those around him.

Patients with multiple myeloma certainly need to have supportive care measures. The one thing patients with myeloma need is something to preserve their bone strength. The use of drugs like bisphosphonates or RANK ligand inhibitors have been shown to improve the quality of life for patients. Patients who get proteasome inhibitors have a higher chance of developing zoster infections, so we should be sure about putting patients on antivirals. For those getting immunomodulatory drugs, especially in combination, we need to be heightened to the possibility of them developing deep venous thrombosis. We need to have these patients on the appropriate strategy to reduce the risk for blood clots. In most cases, the use of aspirin is thought to be adequate. But people who have had prior problems with blood clots are at a higher risk for blood clots than the average patient, and full anticoagulation is often necessary.

Caring for Patients on IRd Therapy in R/R Multiple Myeloma

For patients who are elderly and have multiple myeloma that has relapsed, the challenges are more marked than for those who are otherwise in good health. The choice of regimen has to be tailored to the frailty of the patient. One of the things that we are realizing is important in patients who are older is a proper geriatric assessment. Cursory assessments like performance status using the KPS [Karnofsky Performance Status] scale, the ECOG [Eastern Cooperative Oncology Group] scale, are not sufficient sometimes to get a true sense of what patients can or cannot tolerate. In regard to patients who are having comorbidities and are frail, we need to be sure that we reduce the dose of agents that we use conventionally in patients who are younger and healthier. They often cannot tolerate the full doses of their drugs.

Also, we need to tailor our treatments. Not every patient, honestly, who is older and frailer, will tolerate a 3-drug regimen. In some patients, we have to go back to using 2-drug regimens to balance the toxicity with the efficacy. In older patients, we are often willing to give up some efficacy for better tolerability. The older patients are the ones who often will require drugs to be given serially rather than concurrently. We know that the older patients have a more challenging situation to overcome compared with the younger population that we treat.

We are fortunate in multiple myeloma that we have had a good 2 decades. We have had several new classes of drugs become available to patients that were not available in the past. What is even more exciting is that we have certainly not finished with the discoveries in multiple myeloma. There are a lot of new compounds in clinical trials that look promising.

In regard to the BCMA-directed therapies, the B-cell maturation antigen is a molecule present mainly on plasma cells, so it offers the chance for developing targeted therapies. The BCMA antigen has been targeted using CAR [chimeric antigen receptor] T cells, which have been the subject of great excitement and have results that are unparalleled to any other modality in such a refractory population. But also, BCMA is being targeted using other strategies like antibody drug conjugates, bispecific molecules, and these offer more ready, off-the-shelf access for patients.

Patients also should look forward to the approval of other new classes of drugs in multiple myeloma. Venetoclax, a drug that is already marketed for some leukemias and lymphoma seems, to be active in multiple myeloma, especially for patients who have a translocation involving (11;14). There are other drugs in development, including a drug called selinexor, which is an XPO1 inhibitor that offers patients, even with penta-refractory disease, responses that are approaching about 20% to 25% as a single agent. So I think this is certainly a disease where there is a lot of optimism about treatments in development, and outcomes for patients will improve even further.

Relapsed/Refractory Multiple Myeloma

Impressions of an Elderly Male With R/R Multiple Myeloma

Progress in the Treatment of R/R Multiple Myeloma

Selecting a Treatment Regimen in R/R Multiple Myeloma

Proteasome Inhibitors in High-Risk Multiple Myeloma

Caring for Patients on IRd Therapy in R/R Multiple Myeloma

Novel Treatment Strategies in R/R Multiple Myeloma