Here we have a 74-year-old woman who presents with a severe infection, pneumococcal pneumonia, and ends up in the ICU and has classic features of multiple myeloma. She&rsquo;s hypercalcemic, she has significant anemia, and she has lytic lesions on imaging picked up on the MRI. And also, we have serologic evidence with both the paraproteins by Mspike and light chains and confirmed by bone marrow involvement with 70% plasma cellsso, typical presentation of myeloma in a 74-year-old woman, with also the feature of translocation 4;14 making her more than a low-risk patient.

The risk of multiple myeloma has really evolved over time. We used to use the old Durie-Salmon staging system. One of the biggest limitations of that is that the number of lytic lesions is really very subjective based on how a radiologist might review the imaging. So, the more recent staging is really the International Staging System (ISS), which is based on beta-2 microglobulin and albumin. And so, that stratified patients into stages 1, 2, and 3 with an approximate overall survival of 3, 4, and 5 years, respectively, for 5 years for the low-risk stage 1.

The limitation of the ISS is that it didn&rsquo;t include molecular information, so the revised ISS includes the ISS, the LDH, and also the molecular findings, and so certain molecular findings are very high risk in many diseases like deletion 17p. She happens to have translocation 4;14, which we consider to now be intermediate risk for multiple myeloma. So, by a revised ISS stage, we would need to look at all of those features to determine her risk status.

Risk Assessment of Multiple Myeloma

In terms of the role of autologous transplant in high-risk patients, it&rsquo;s a very difficult question to answer, because high-risk patients probably make up about one-third of newly diagnosed patients. And so, that means that when we do clinical trials, only one-third of the patients will be high risk in the 2 different arms. So, we really can&rsquo;t power studies to definitively answer this question, and also there&rsquo;s the logistics of screening a patient and enrolling them and then finding out their molecular risk after the fact.

I think the current thought process in myeloma is that everybody benefits from induction therapy and consolidation with transplant, based on a

paper the French presented showing that an early transplant leads to significant prolongation of progression-free survival by almost 14 months relative to delayed transplant. Then the question is, of course, maintenance therapy, and also who&rsquo;s the candidate for transplant. So, for high-risk patients, we know that even with good induction therapy and transplant, they will relapse sooner, and so there&rsquo;s work being done on more aggressive maintenance therapy beyond just a single agent. And there are some preliminary data showing that double-agent therapy might be better.

For this particular patient, of course, the question is, is she eligible for transplant? And that&rsquo;s a difficult question. It really depends on the cancer center and where the patient is being diagnosed and treated. Medicare pays for transplant up to age 80. However, because we need to reduce the dose of melphalan-conditioning chemotherapy for transplant, anybody over the age of 70 is going to get a slightly lower dose of the chemotherapy. And given all of the exciting drugs that we have now at our disposal, the risk/benefit ratio may be slightly different. And so, many patients above the age of 70, if they have a good response to the initial therapy, may not necessarily benefit from transplant. But, again, the data for this particular subgroup are limited in the era of current modern therapy.

I think the unmet needs in multiple myeloma in general are frail, elderly patients who are often not enrolled in clinical trials. Second would be renal insufficiency, and the third is high-risk patients, because those are the 3 groups of patients who are probably bringing down the median overall survival curves. And so, if we could improve the outcomes of these patients, I think we would then make the entire disease look better, because it&rsquo;s not just the selected, cherry-picked young, fit patients who are really perfect. And the reality is that myeloma is often a cancer of the elderly with a median age of 65, although at our institution, our youngest was diagnosed at 18 and the oldest is over 100. So, when you have such a heterogeneous disease, we really have to be mindful of personalizing the therapy for that patient. And so, for this patient particularly being high risk, it&rsquo;s really important to be aggressive with therapy because in older patients, often you don&rsquo;t have as many chances to salvage because of their comorbidities. You have 1 good shot to get their disease under control.

Transplant and Unmet Needs in Myeloma

There is a recently published study in the

comparing VMP with daratumumab/VMP. And the reason this is an important study is that historically, there&rsquo;s this perception that elderly patients cannot get more than 1 drug because they&rsquo;re going to have more toxicity. But I think we have to be mindful again of what drugs we&rsquo;re talking about. If you combine drugs with overlapping toxicity, you&rsquo;re going to have more side effects. And so, VMPwhich is not as widely used in the United States, but it&rsquo;s a very widely used regimen globally&mdash;basically is bortezomib/melphalan/prednisone, and that was already shown in the VISTA study to be superior to melphalan/prednisone (MP), which is an oral doublet regimen.

So, we know that VMP resulted in better overall survival than MP, so the question is, can we now further improve upon VMP? And in this randomized study, transplant-ineligible patients are randomized to either VMP or the addition of daratumumab in standard dose and schedule. And so, what this study showed is that, very impressively, all of the efficacy endpoints were met. So, we saw improvement in response rates, improvement in CR rates, improvement in MRD negativity, and an improvement in progression-free survival. These are really encouraging data for a population, as we had said, that is historically an unmet medical need, which is the elderly patient population. So, to see improvements in outcomes in this population is really exciting.

For this ALCYONE study, when we compared daratumumab/VMP with VMP, the safety was also very encouraging in terms of that really, there were no significant differences in cytopenias. And the main difference was that there was a slight increased rate of infection. But, again, this is an elderly population with a lot of comorbidities. Infections are very common in myeloma, but I think it does bring to mind that we need to be very aggressive with elderly patients in terms of supportive care like growth factors, antibiotics, and, potentially, the use of intravenous immunoglobulin if somebody is very hypogammaglobulinemic.

Myeloma: Impact of the ALCYONE Trial

Whenever we talk about a clinical trial, we should compare the eligibility criteria to the patient sitting in front of us in clinic to see if this patient would have been ineligible and if the risk/benefit profile observed from this study would be applicable to this patient. And the typical features that would make somebody ineligible for clinical trial in myeloma would be organ function. So, renal dysfunction would be a big issue, and up to one-third of myeloma patients can have renal insufficiency. And so, in this particular regimen, the drug that would be most significantly affected by renal dysfunction would be melphalan. Daratumumab, bortezomib, and prednisone can all be given safely in renal dysfunction. It&rsquo;s really the melphalan that would need to be dose adjusted. Second would be other major comorbidities like cardiac dysfunction, which is often excluded from clinical trials. But one of the limitations thereand there is a lot of talk in ASCO, as well&mdash;is that we need to be generalizing our clinical trial eligibility because if we cherry-pick patients, and particularly in myeloma, because our patients are older, older patients are going to have more comorbidities. So, if we become very selective, it limits the generalizability.

In this particular patient, we don&rsquo;t have any major exclusionary criteria for her not being in the study. And then the other big thing in myeloma clinical trials is probably blood counts. So, patients&rsquo; baseline blood countsin particular, neutrophils and platelets&mdash;need to meet the eligibility criteria. In this case, this patient would be appropriate for the enrollment in ALCYONE study.

Daratumumab/VMP may be available very soon. The FDA gave it a very favorable and high priority review earlier this year, and we may be hearing in the next few months about the approval. I think the ramification of the approval will be interesting in the United States because, for example, when VMP was approved many years ago, oncologists took that to be able to use bortezomib frontline, but many people weren&rsquo;t necessarily giving the melphalan with it. And so, in the United States, sometimes we need an approval in a particular line of therapynewly diagnosed, relapsed, relapsed/refractory. Once it&rsquo;s approved in that line of therapy, you could potentially modify the regimen to suit your patient. So, for example, if daratumumab/VMP were approved in the United States and there&rsquo;s a patient who had renal dysfunction, a practicing oncologist could say, &ldquo;I don&rsquo;t think the melphalan is appropriate for this patient, so I&rsquo;m going to give a more modified version of the drug, the regimen, for my patient who is sitting here in front of me.&rdquo;

So, I think we&rsquo;ll have to see how insurers and payers will deal with the approval in terms of allowing modifications. But I think it&rsquo;s also very interesting that VRD, which is one of the most widely used regimens for induction in the United States, did not have any phase III supporting data until pretty much about a year ago, and yet it has probably been the regimen of choice for 7, 8 years. So, I think sometimes what happens in oncology is that very exciting combinations and preliminary phase II data are so compelling that physicians change practice. And if the payers are approving it, then those regimens become standard of care well before the pivotal phase III studies approve that particular regimen.

Use of VMP + Daratumumab in Myeloma

The follow-up for multiple myeloma is pretty well standardized. First, we look for serologic remission with the SPEP (serum protein electrophoresis), the immunofixation, the free light chains, and those patients who have urine protein. So, once we see that the serologies are all converting to negative, ideally, the next thing that should also be considered is imaging, because for the patient who may have presented with a lot of bone disease, we want to make sure that the bone disease is all resolved. And so, this is where PET scans and MRIs are much more useful than X-ray, because once the bone is damaged on plain X-ray, even if the disease is in remission, it may not completely normalize and typically does notwhereas PET scans will go from FDG-avid to FDG-not avid or MRI lesions can improve with treatment.

So, if a patient has serologic remission, radiologic remission, then a bone marrow could be done to determine if a patient is minimal residual diseasenegative. And I mention the imaging because the bone marrow is just a random sample, and if you get an MRD-negative result but then the patient still has radiologic disease, that is not the same as somebody who has negative imaging and is MRD-negative. And with the second patient, we&rsquo;re much more confident that we really achieved a good remission.

So, in the ALCYONE study, it&rsquo;s impressive because even in an elderly population, almost one-quarter of patients attained MRD negativity. The use of MRD is really important in this type of setting because there&rsquo;s no need for MRD in a penta-refractory patient who&rsquo;s heavily pretreated, because you want to see that the overall survival is better, and the progression-free survival should speak for itself. As you move up into these newly diagnosed settingsbecause myeloma patients are living longer and longer&mdash;the follow-up for showing that somebody is MRD-negative, a particular arm is better than another and would be really prohibitively long. And so, MRD can be used as a surrogate endpoint specifically in this kind of newly diagnosed setting or in a maintenance setting, where this is the earliest sign that we&rsquo;re really going to have impact on long-term outcomes.

Myeloma: Follow-Up and MRD Testing

The future for this particular patient population that I think is really exciting is going to be daratumumab/VRD. And the reason that I bring this up is that if you go back in time, we know that with these melphalan-based regimensalthough they are used globally because of the low cost of melphalan&mdash;the problem is that melphalan can be slow to act, it can be stem cell toxic, it&rsquo;s really cleared, it doesn&rsquo;t necessarily work in high-risk disease, and it can lower blood counts. So, it has a lot of features that American oncologists don&rsquo;t like, and since we have the ability to use many drugs, we often don&rsquo;t use melphalan. And so, when we had the first study that compared lenalidomide/dexamethasone to melphalan/prednisone/thalidomide (MPT), that showed definitively that lenalidomide/dexamethasone was superior in terms of progression-free survival and efficacy outcomes to MPT, showing that RD was probably the better regimen for elderly patients.

Then came the SWOG study that was recently published, which showed that when you take patients without an intent to transplant and do VRD plus RD, the VRD led to a better response rate, progression-free survival, and overall survival. And so, for that reason, VRD is really the preferred induction regimen. The problem with the SWOG study, though, is that it wasn&rsquo;t restricted to elderly patients or transplant-ineligible patients. It was just without the intent to transplant. And so, there were relatively few patients who were above the age of 65. And also, what we really need to think about for older patients is safety, and VRD in the SWOG study was given with twice-weekly bortezomib, standard-dose lenalidomide, and standard-dose dexamethasone.

So, I think for transplant-ineligible patients, we have already published that in our series, we looked at about 120 patients at our institution who are over the age of 70, and we found that the best outcomes really occurred with VRD. But here we give bortezomib weekly; lenalidomide is dose reduced based on renal function, age, and lower doses of steroids, and we really had very impressive progression-free survival of 36 monthsvery high response rates. We hadn&rsquo;t reached a median overall survival.

I think this is where daratumumab/VRD will be very exciting, because previous studies have shown that 4 drugs are not always better than 3 drugs. For example, the addition of cyclophosphamide to RVD did not improve outcomes and led to more neutropenia, and so not all 4 drugs are better than 3 drugs. However, what&rsquo;s unique about daratumumab is its clean side effect profile. It&rsquo;s a monoclonal antibody, so it has been safely combined with both proteasome inhibitors, both IMiDs, all 3 IMiDs, cyclophosphamide, and melphalan. And so, we think that this quadruplet is different from a standard quadruplet, and we already see that the daratumumab/VMP has shown superiority to VMP.

So, I think there&rsquo;s a lot of interest in this daratumumab/VRD. There is a randomized frontline study comparing VRD with daratumumab/RVD in transplant-eligible patients, so we&rsquo;ll see what those data look like. But at our institution, we&rsquo;re very excited about the investigator-initiated study with daratumumab/VRD with dose attenuation for transplant-ineligible patients. And, of course, the other very exciting thing that will be coming forward would be the daratumumab subQ. And that, particularly for elderly patients, will be really impressive, because there&rsquo;s going to be super well tolerated, with minimal volume, minimal time in the clinic. So, I think the daratumumab subQ data are really encouraging, and I think we&rsquo;re all excited to see how that daratumumab/VRD with the subQ daratumumab will look in this elderly population.

Treating High-Risk Multiple Myeloma

Risk Assessment of Multiple Myeloma

Transplant and Unmet Needs in Myeloma

Myeloma: Impact of the ALCYONE Trial

Use of VMP + Daratumumab in Myeloma

Myeloma: Follow-Up and MRD Testing

Potential of VRD + Daratumumab in Myeloma