We have a 61-year-old female who was diagnosed with symptomatic multiple myeloma. As a result, she was started on initial induction chemotherapy. Her staging was stage 2, so she got lenalidomide, bortezomib, and dexamethasone (RVD triplet therapy), followed by transplant (as consolidation therapy) and lenalidomide (as maintenance therapy). Of note, she did have translocation t(14;16 at diagnosis), and, therefore, the decision was to actually proceed with the maintenance therapy. Her remission lasted quite a long timefor approximately 5 years.

This 61-year-old female is relatively typical for multiple myeloma. The median age of diagnosis is approximately for patients in their mid-60s. However, it&rsquo;s a very heterogeneous disease. Our youngest patient was age 18, and our oldest is over age 100. That heterogeneity also adds to the complexity of treating this cancer, because patients will come with various levels of comorbidities. Particularly, in the older patients, we now know that there&rsquo;s increasing cardiac comorbidities that can affect their tolerance of different therapy and eligibility for transplant. So, it&rsquo;s important to think about the patient&rsquo;s myeloma in the context of their age and other medical conditions.

Multiple myeloma, as we know, unlike solid tumors, can&rsquo;t be staged as localized or diffuse because it&rsquo;s a bone marrow disease. The initial staging system used in the 1970s was the Durie-Salmon Staging System. While that was an important advancement, one of the criticisms of that was in regard to the lytic lesions that are detected by radiologists on skeletal imaging. The problem with that is a radiologist may say there are 4 lesions, while another may read it as 6. Therefore, you have some upstaging. It didn&rsquo;t really seem to be reproducible, as much, and we didn&rsquo;t get as good of a separation. So, along came, in 2005, the International Staging System, which was an effort to try to have a more simple staging system. This is based on beta 2-microglobulin and albumin, and it&rsquo;s globally reproduced and very simple. This allowed separation into stages 1, 2, and 3 with associated median survivals of 4, 5, and 3 years, respectively.

While this was a big advancement, we now know that in all of oncology, molecular information is very important and it helps risk stratify patients even further. So, the latest version of myeloma staging came out in the

, in 2015, by Dr Palumbo, et al., This staging system includes the International Staging System (based on beta 2-microglobulin and albumin), but it now also incorporates LDH (lactate dehydrogenase) and molecular risk.

In particular, high LDH is considered high risk, and certain findings by the FISH (fluorescence in situ hybridization) test, including translocation t(4;14), translocation t(14;16), and also deletion 17p, are typically considered  high risk. So, now we integrate all of that. The reason this is an advancement is now we can segregate patients into median overall survival for stage 1 (of not even reached), stage 2 (of approximately 7 years), and stage 3 (of only 3.5 years). Clearly, this illustrates that it&rsquo;s this high-risk population that still has an unmet medical need, despite all of our new drug approvals in myeloma.

Diagnosis of Stage 2 Multiple Myeloma

Symptomatic multiple myeloma needs to be treated (unlike smoldering disease, which is more controversial). In this population, because they presumably have hypercalcemia, renal insufficiency, anemia, or lytic disease, we want treatment that&rsquo;s going to be rapidly effective at reducing those symptoms, also allowing for a deeper remission and not interfering with stem cell collection.

With those objectives in mind, studies have shown that doublet therapy clearly works, but triplet therapy is better. For the longest time, a lot of physicians in the United States have been using the triplet therapy combination of lenalidomide, bortezomib, and dexamethasone (RVD), without any substantiating phase III studies. RVD was based primarily on phase II data until this past year when the SWOG S0777 study was published. This study compared newly diagnosed symptomatic patients to be randomized to either RVD triplet therapy or RD (lenalidomide and dexamethasone) doublet therapy. This showed a significant improvement in response ratesparticularly deep responses, PFS (progression-free survival), and OS (overall survival). Yet, there was toxicity noted with this triplet regimen. There was tripling of both neurologic side effects as well as gastrointestinal side effects.

However, it&rsquo;s important to remember that when this study was designed, bortezomib was being given intravenously, twice weekly. We know that&rsquo;s not as well tolerated as subcutaneous therapy, because we know that the toxicity of bortezomib is related to C

, and not in the area under the curve. So, by giving it subcutaneously, we know that you can get comparable efficacy without that high C

so, less toxicity. This is at least putting the toxicity aside, which we think is going to be mitigated by subcutaneous injections. We now have phase III, randomized study level evidence that triplet therapy is better than doublet therapy for induction in newly diagnosed patients.

Now, what else could we do besides that regimen? We could play around with the individual drugs, potentially. In Europe, where there&rsquo;s a lot more cost constraints and drug access issues, perhaps the lenalidomide is sometimes replaced by thalidomide. But, we do believe that lenalidomide is a more potent agent. There are also studies being done to replace bortezomib with carfilzomib. KRD (carfilzomib, lenalidomide, and dexamethasone) is a very active regimen that was studied by an Italian group. This study was called the FORTE study. KRD was compared to carfilzomib, cyclophosphamide, and dexamethasone (yet, another combination). Some folks do use cyclophosphamide instead of the IMiD (immunomodulatory imide drug). And that study showed that KRD did result in deeper responsesboth VGPR (very good partial response) and better, as well as CR (complete response). However, it did also slightly increase toxicity (both rash and minor LFTs [left ventricular functions]), and slightly decreased stem cell collection. So, I think the triplets do seem to be the way to control newly diagnosed myeloma. Definitely, a PI (proteasome inhibitor) is part of that, and the IMiD seems to be preferable to the alkylating agent.

There was another study that compared VTD (bortezomib, thalidomide, and dexamethasone) to VCD (bortezomib with cyclophosphamide and dexamethasone), and that showed slight superiority with VTD in terms of depth of response. So, PI, IMiD, and steroid seems to be optimal. But, there are, I would note, some patients where cyclophosphamide may still have a roleprobably for somebody with acute renal failure, perhaps an inpatient scenario where it can be difficult to get the IMiD delivered promptly, or for somebody who is very bed bound or has poor performance status (where they have a higher thrombotic risk, making anticoagulation potentially challenging). I think it&rsquo;s nice to have choices, but clearly, the SWOG S0777 study really informs induction therapy, showing that RVD is a really great frontline regimen.

We now have the evidence for triplet RVD therapy, but the question is, what do we do next? Can we go beyond that? The EVOLUTION study that was done by the Mayo group showed that adding cyclophosphamide to do a 4-drug regimen didn&rsquo;t significantly increase responses, but did result in increased neutropenia. So, it doesn&rsquo;t seem like a quadruplet option, at least that particular quadruplet option, is better than the triplet therapy. The question is, of the new monoclonal antibodies that have been approved (elotuzumab, the anti-CS1 monoclonal antibody, as well as daratumumab, the anti-CD38 antibody), how might these factor in with the RVD backbone? And so, at the ASCO Annual Meeting, we had 2 different studies that were presented. Elotuzumab was added to RVD, and it did seem to result in very high response rates. But, there was a concern about a slight increase in infectious complications. Daratumumab was added to carfilzomib, lenalidomide, and dexamethasone (KRD), and that regimen was also generally well tolerated. The main toxicities were similar to KRD, and the depth of response was quite impressive. However, these are both relatively small studies of 20 to 30 patients or so, and primarily, we only have response rates. We don&rsquo;t yet have those PFS-type of endpoints. These quadruplet therapies with monoclonal antibodies, up front, will need to be studied further. This may be particularly important in non-transplant eligible patients, where there is not an ability to transplant to consolidate. So, we&rsquo;ll have to see how these regimens pan out in the future.

RVD Induction Therapy for High-Risk Myeloma

If we agree that triplet therapy is probably optimal as induction therapy, then the question is, if these responses are so good, what is the role of transplant in 2017? That question was kind of hard to answer. We all had a feeling that if somebody had such a great response, what was the role of transplant? Again, we need data. Luckily, the IFM/Dana-Farber (IFM/DFCI) study has really helped us understand this. This study took everybody with newly diagnosed symptomatic myeloma that was transplant eligible, and gave them 3 cycles of RVD (bortezomib, lenalidomide, and dexamethasone) as induction therapy. Everybody had cyclophosphamide mobilization, and then half were randomized to transplant with RVD consolidation and lenalidomide maintenance. In contrast, the control arm had, after collection, 5 cycles of RVD consolidation and then a year of lenalidomide maintenance.

In this study, we found that the depth of response was better with transplant consolidation, and the PFS (progression-free survival) was significantly prolonged by almost 14 to 15 months. It didn&rsquo;t seem to matter because one might think, &ldquo;Well, perhaps these were only for people who didn&rsquo;t have that great depth of response?&rdquo; But, this was regardless of age, regardless of risk, and regardless of depth of response to induction therapy. So, if we take that data at face value, it suggests that early transplant is not a bad option, and it may result in better outcomes. The limitation, though, is that an overall survival was not differentit was about 43 months of follow up. That&rsquo;s important because we now know that median overall survival in myeloma (particularly for standard risk and favorable risk) can be well over 7 to 10 years. This follow up may not be long enough to understand the OS (overall survival) benefit.

The other important caveat is that this was the French version of the study, where lenalidomide maintenance was terminated at 1 year. The American counterpart to this uses lenalidomide maintenance until progression. It&rsquo;s possible, then, that we may see less difference in PFS if we continue lenalidomide maintenance until progression. So, the jury is out on that approach. But, in 2017, what do we tell our patients? We present them this data that consolidating that first induction therapy with a transplant seems to result in better outcomes. Is it mandatory? Perhaps not, since there&rsquo;s not yet an OS difference. However, I think that most transplant centers and physicians would strongly encourage early transplant.

Based on the data from the IFM/DFCI study, which supports early transplant, this patient, who is 61 years old, is transplant eligible, seems to have had a good response to therapy, and is someone in whom there shouldn&rsquo;t be any problems collecting stem cells for, would likely be a good candidate for both stem cell harvesting and proceeding with stem cell transplantation as a consolidation modality.

Consolidation Autologous Transplant for Myeloma

Maintenance therapy after transplant is, again, guided by evidence, and we had 2

papers (1 from the United States, 1 from France), where everybody who had transplant was then randomized post-transplant to either lenalidomide or placebo. Those studies were both quite consistentthe PFS (progression-free survival) without maintenance therapy was approximately 2 years, and with the addition of maintenance therapy with lenalidomide, that increased to about 4 years. And so, that&rsquo;s pretty clear data and it&rsquo;s consistent between both studies.

The OS (overall survival), of course, is interesting and important. The OS in the American study showed an improvement, but the French version did not. Interestingly, you probably would have expected the opposite, because it was the American study that allowed crossover. If patients were randomized to placebo, they could cross over to lenalidomide maintenance at the time of progression (which would clearly decrease your ability to detect an OS difference). But, the fact that the American study didn&rsquo;t show that really does suggest that the PFS benefit does eventually translate into an OS benefit, which is what we usually think about in oncology. The whole reason we use these surrogate endpoints is because response rate typically correlates with PFS, and PFS typically correlates with OS. That&rsquo;s why the FDA has allowed PFS to be used as a surrogate endpointnot just in myeloma, but in other tumors. That would support that premise.

Now, the push back some people have for maintenance therapy is, are you bringing out resistant clones? By using lenalidomide maintenance, might you be selecting myeloma clones that are difficult to treat? My response to that would be, if that were truly the case, then how are we seeing an OS benefit with lenalidomide maintenance in the United States study? And, secondly, we need to also be mindful that when you&rsquo;re looking at OS, this is not the primary endpoint of the study. The study only defines that initial therapy. The minute the patient progresses, you lose all the randomization and controlling for confounding variables, and that&rsquo;s where access to the drug is differentiated from across the Atlantic.

In the United States, when patients were progressing on lenalidomide maintenance, a lot of them could be salvaged appropriately with bortezomib maintenance, etc. In France, some of those patients who progressed on lenalidomide maintenance went on to get more IMiD (immunomodulatory drug) maintenance which, in 2015, was either more lenalidomide or more thalidomide. I&rsquo;m sorry, from 2005 to 2012when these were done. I think it&rsquo;s important to remember that OS depends not only on the initial randomization, but on subsequent salvages. And so, you may lose that benefit of the initial randomization.

And then, the last important point to make about lenalidomide maintenance is toxicity. Generally, it&rsquo;s well tolerated. There are studies that show that patient reported outcomes and quality of life measures don&rsquo;t seem to drop significantly. However, we do know that there is a slight increase in secondary malignancies. Both studies showed thatthe French study and the United States study. The rates can be anywhere from 1% to 3% in the control arm, and up to 6% to 8% in the interventional arm.

And so, what do we do with that data? Again, the PFS and OS data from lenalidomide maintenance speaks for itself. However, we also do recognize that patients need to be keeping up with age appropriate cancer screening procedures like mammograms and colonoscopies, because the malignancies that the patients got were all over the board. They could be hematologic- or solid tumor-related. But, in the end, many of us feel that the lenalidomide maintenance benefit does seem to override the minor risks of lenalidomide maintenance. However, at the end of the day, it&rsquo;s always a patient-specific decision.

Lenalidomide maintenance probably has the most data, and there is now a recent meta-analysis showing that, across several studies, the OS benefit was maintained. And now, lenalidomide maintenance is on-label, per the FDA, because of this OS benefit. Are there other alternatives to lenalidomide maintenance? There are some smaller studies with bortezomib maintenance. Some of them have a complicated study design because rather than just a maintenance randomization, they also deferred in the induction part of the therapy. But, certainly, bortezomib maintenance is another option.

One of the limitations is, because it&rsquo;s a parenteral drug, it can be challenging to administer on a long-term basis. There are numerous studies coming out looking at ixazomib, which is the oral proteasome inhibitor (PI), in maintenance settings (given the convenience of the drug). Also, daratumumab, the monoclonal antibody, will be studied in the maintenance setting. Even now, we feel that lenalidomide maintenance, while important, may not be enough for high-risk patients, because those patients still seem to do worse compared to their standard risk counterparts.

The Emory group presented a retrospective study that showed that combined maintenance with lenalidomide, bortezomib, and dexamethasone can actually result in much better PFS outcomes. Admittedly, we don&rsquo;t have a randomized prospective study to support that. But, if somebody is really high-risk, consideration should be given to doing more than lenalidomide maintenance in combination therapy.

So, going back to our 61-year-old female, she had the triplet therapy, stem cell transplant consolidation treatment. She did have translocation t(14;16), which is considered to be a high-risk feature. Therefore, lenalidomide maintenance would be appropriate. One might also consider PI-based maintenance to also be appropriate, if somebody had translocation t(4;14), given the data that PIs may be better or may be able to overcome that high-risk finding. But, for this patient, lenalidomide maintenance would be a very reasonable approach.

Post-Transplant Lenalidomide Maintenance for Myeloma

After stem cell transplant, typically we do restaging at somewhere between day 90 to 100, and that would include the usual labs, a 24-hour urine collection, imaging to ensure that there&rsquo;s no radiologic disease, and, finally, the marrow sample. In bone marrow, we now not only look, histologically, to see if there&rsquo;s any clonal plasma cells left, but there&rsquo;s also increasing interest in using more sensitive methods to look for minimal residual disease (MRD).

This is an important area of investigation, and there&rsquo;s 2 major types of MRD testing. One is flow-based, and the other one is next-generation sequencing. There are some pros and cons to both of them. Next-generation sequencing has the advantage that it is not as variable dependent. For flow cytometry, when the aspirate is pulled out, we have to try to get it to the lab quickly because the plasma cells are labile. And then, we need to also check how many cells are being counted and how many markers are being tested. With all of those quality control issues, it&rsquo;s not as well standardized. Next-generation sequencing, in some ways, is more easily standardized. However, the caveat is, you do need that initial clone from the patient to be able to detect that in the minimal residual disease state. Flow cytometry doesn&rsquo;t require that. Every patient, theoretically, is evaluable for flow, but if a patient didn&rsquo;t have the initial clone for next-generation sequencing, they may not be evaluable for MRD.

The other big difference between them is the sensitivity of the test. It&rsquo;s thought that next-generation sequencing can get up to 10

, or 1 in 1 million. Whereas, with flow cytometry, depending on the data, the number of the cells counted and the channels or the number of antigens tested can be 10

. So, those are some approaches, and the question is, as a community doctor or even for any physician, one of the things we&rsquo;re always taught in medical school is if you do a test, how will it change your management of your patient? And I would say, in 2017, we don&rsquo;t have an answer for that. That&rsquo;s why I think this is still in research.

And part of it is, as somebody once said, we know if somebody has a hemoglobin of 8 g/dL, it&rsquo;s going to be pretty reproducible from lab to lab (when you go around the country). We know that patient is quite anemic. But, when you have a test like flow cytometry, which is so user dependent, is maybe subject to so many quality control issues, and is not yet well standardized, you may very well get different results at different centers and at different time points (perhaps even from different sides of the marrow). We didn&rsquo;t even mention that the marrow really is contingent on all the other tests being negative. So, in other words, you need to have serum being negative, urine being negative, and very importantly, radiologic studies being negative. What if your marrow is negative but there&rsquo;s still an osseous lesion that&rsquo;s lighting up on the PET scan?

There is this well understood concept of macrofocal disease, where you can have little pockets of myeloma but the marrow may be negative. We don&rsquo;t want to be making decisions based on incomplete data. So, I would say that this is an important area of investigation. And the other caveat that we didn&rsquo;t mention yet about MRD is the importance of molecular risk. I would like to think that if MRD is negative, it means the same thing for any patientthat it&rsquo;s a great result. However, we know that MRD negativity may not mean the same thing in high-risk patients, which means we have to really think about those patients. And even if it&rsquo;s MRD-negative, we can not necessarily assume that all is well.

And lastly, getting back to the concept of changing of therapy, it would be nice to know, if a patient was MRD-positive, we should escalate the therapy? And perhaps equally interesting, if you have a low-risk MRD-negative patient, can we stop therapy? I don&rsquo;t think we have any prospective studies to answer these questions, but it&rsquo;s an area of investigation. And probably, in the community, if a patient was having difficulty tolerating maintenance therapy for some reason, or was averse to doing it, and you were doing the MRD test, perhaps it would be reasonable for that patient to not do maintenance therapy. But again, acknowledging this is outside of evidence-based practice.

So, going back to this patient, whether she was MRD-negative or not, in 2017, we don&rsquo;t know that we would change our management of lenalidomide maintenancethe use of lenalidomide maintenance or the duration of lenalidomide maintenance.

This patient (who was taking lenalidomide maintenance) was doing quite well. She was working full-time. She had grade 1 neuropathy but actually had a good quality of life. And then, in August of 2016, we noticed that on laboratory testing, although her calcium was normal, her creatinine did bump up to 1.3. She did become slightly anemic to a hemoglobin of 10.3 g/dL. She did not have any known new bone lesions, but her paraprotein testing also showed that her free light chains were rising and her serum M-spike was now detectable at 1.3. She clearly has had a relapse of her myeloma on lenalidomide maintenance, and the question becomes, what do we do now?

The progression of myeloma can come in 2 flavors, broadly speaking. One is a biochemical progression, which would be purely paraprotein related. And by myeloma clinical trial criteria, the numbers that we would look for typically would be an M-spike of, depending on the isotype, 0.5 for IgA (immunoglobulin A), 1.0 for IgG (immunoglobulin G), free light chains becoming more than 100 mg/L, or the 24-hour urine collection now showing more than 200 mg/day of Bence-Jones protein. You can have patients with that isolated biochemical relapse, which may be very slow and indolent. Conversely, you can have a very fulminant relapse with the CRAB (calcium, renal failure, anemia, bone lesion) symptoms that we were just discussing. And perhaps, even worse, you can have extramedullary disease, high LDH (lactate dehydrogenase), and circulating plasma cells. So, we have to understand that the relapse of myeloma can come in that entire spectrum, and it&rsquo;s important to consider that when making decisions about treatment.

MRD Assessment of Response to Myeloma Therapy

In trying to decide how to treat a patient with relapse, the first question is, where is this patient on that continuum of purely biochemical relapse to fulminant disease? Not everybody with mild biochemical relapse, which isn&rsquo;t even fully detectable or fully measurable by IMWG (International Myeloma Working Group) response criteria, needs immediate therapy. That type of patient could potentially be watched for a few months longer until we do have symptoms. Conversely, if the patient has symptomatic disease, we need to obviously start therapy immediately, regardless of whether or not it&rsquo;s measurable.

It&rsquo;s important to know that for some patients who have a heavy chain component (an IgG [immunoglobulin G] kappa M-spike of 1.3 at the time of initial diagnosis), by the time they relapse, they may have that concept or free light chain escape. They only have kappa light chain disease. So, it&rsquo;s important that community doctors check all of those myeloma labs in patients on maintenance therapy, so that we&rsquo;re not missing that type of relapse.

If somebody had this symptomatic relapse, as our patient has, then I think the first question is, what kind of regimen do we use? Fortunately, in myeloma, we&rsquo;ve had a plethora of relapse studies. In fact, we&rsquo;ve had 7 phase III studies and 1 randomized phase II study. It&rsquo;s unprecedented, I think, in oncology to have so many studies to choose fromphase III, randomized, high-quality studies that have all led to the approval of these agents.

The first thing I think that we need to do is break these studies down into either a lenalidomide-based backbone or a bortezomib-based backbone. And that&rsquo;s important because this patient, for example, is on lenalidomide maintenance therapy. By definition, her progression on lenalidomide maintenance would make her ineligible for all 4 studies that required lenalidomide sensitivity. There was a control arm in those 4 studies where half the patients were only going to get lenalidomide and dexamethasone, and that might not be appropriate if somebody is clinically relapsing (to just give them a little bit more lenalidomide and dexamethasone). We do that, sometimes, outside of studies because if it&rsquo;s a biochemical relapse, perhaps we can milk some more mileage. But, in a prospective clinical trial, that would not be appropriate, especially when you have a randomization regimen there that we need, depending on the outcomes, both arms to be as good as possible.

For this patient, if we were practicing evidence-based medicine, we couldn&rsquo;t use those 4 studies. So, we would then go to the PI (proteasome inhibitor) backbone studies. For pretty much all of these studies, we have a daratumumab-containing regimen, a carfilzomib-containing regimen, and an elotuzumab-containing regimen. In the PI studies, there&rsquo;s also panobinostat. So, to summarize, we have daratumumab/VD (bortezomib and dexamethasone) versus VD; KD (carfilzomib and dexamethasone), which is high-dose carfilzomib at 56 mg/m

versus VD; and elotuzumab/VD versus VD, although this is a randomized phase II trial but also sizable150 patients or so. And then, lastly, we have panobinostat/VD versus VD.

So, we have 4 studies, and it&rsquo;s important to remember that, as we were taught in medical school, it&rsquo;s always tempting to compare cross studies. Let&rsquo;s just take the one with the best response rate, with the best PFS [progression-free survival] and the best OS [overall survival], and then, boom, apply that to everybody. The problem with that is these studies are not balanced, and there&rsquo;s always going to be differences between the eligibility criteria. Were they relapsed at the time of entry? Were they actually refractory? How old were these patients? What is their risk status, both international stage and molecular risk? How many lines of prior therapy did they have? Were they being enrolled in ex-United States or United States trials, where the initial therapies may have been very different?

I bring up all of those factors because we really can&rsquo;t compare directly to median PFS, for example, across all of these studies. And although it&rsquo;s intellectually the easiest to do, it&rsquo;s also intellectually the laziest to do. What we really need to do is look at hazard ratios, which at least gives you the relative value added within each study for the novel agent versus conventional option. And what&rsquo;s interesting is, when you look at these hazard ratios for all of these studies, they pretty much all line up in this 0.6 to 0.7 range with 1 exceptionthat&rsquo;s daratumumab. There is daratumumab/RD (lenalidomide and dexamethasone) or daratumumab/VD. In this case, reflecting on the CASTOR study that compared daratumumab/VD versus VD, the hazard ratio was quite impressive&mdash;0.39 (or, the other way of saying that is 61% reduction in the risk of progression or death).

That&rsquo;s quite impressive and, admittedly, the follow-up is not going to be as long as those other studies. So, we don&rsquo;t yet see OS benefit. That&rsquo;s going to require longer follow up. But, I think that&rsquo;s why, for that reason, people are so interested in daratumumab-containing regimens. These hazard ratios are quite impressive. Again, it&rsquo;s not to say that those other regimens may not be appropriate, and they&rsquo;re all excellent regimens. They all will work very well. But, if you had to pick what would be the best option in terms of evidence-based, that&rsquo;s probably one of the most compelling. And so, that would be the approach for this patient, given that she was in lenalidomide maintenance failure.

Now, it&rsquo;s also important to talk about the other options. There was another group of 4 studies, that are equally compelling, that have the lenalidomide-based backbone. Again, we have daratumumab/RD versus RDthis was demonstrated by the POLLUX study. We have carfilzomib/RD versus RD, which was demonstrated the ASPIRE study. We have elotuzumab /RD versus RD, demonstrated in ELOQUENT. The last study is ixazomib/RD versus RD. So, we now have 4 more regimens that are lenalidomide-containing. How do we pick? Again, the same caveats apply. There&rsquo;s differences in patient populations, and it&rsquo;s easy to just say, &ldquo;I&rsquo;m going to take the one with the highest PFS.&rdquo; But that&rsquo;s, again, not the right way to do it. And if we look at the hazard ratios, yet again, they kind of stack up in this 0.5 to 0.7 range with the notable exception of the POLLUX study, where daratumumab/RD versus RD gives you a hazard ratio, again, in the 0.3 range. This, again, shows a much better reduction in the risk of progression or death. It&rsquo;s a very good regimen to consider for patients who are progressing.

This is where that generalizability of a study to the patient is so important. The hazard ratios that we just talked about for the lenalidomide-containing regimen may not be applicable to this patient because she&rsquo;s had lenalidomide maintenance failure. So, if we were to try to add the third drug to her lenalidomide/dexamethasone regimen, we may not be able to guarantee that the benefit for her would be as good as it was for the other patients in that study who, by definition, could not be lenalidomide-refractory (including those not refractory to lenalidomide maintenance). It&rsquo;s nice that daratumumab and carfilzomib are both regimens containing a PI backbone as well as an IMiD (immunomodulatory drug) backbone. It&rsquo;s nice to have all these options. And, at the end of the day, the choice of a regimen is really going to be patient specific, as well.

We need to think about this patient&rsquo;s age, frailty, comorbidities, neuropathy rates, and renal functionand those are host factors. The second thing to consider is the disease factors, which are not only related to the burden of the disease and symptoms, but also biology. Is there a molecular risk? And lastly, we need to think about therapies, including what they had been treated with before. How well did they respond? What toxicities did they have? Is this therapy going to be parenteral or oral? Is it going to be a combination or single-agent regimen? What is the cost of this drug, both to the healthcare system and also to the patient (in terms of out-of-pocket costs)? I think we have a lot of factors to consider, and, at the end of the day, this is why we say medicine is an art and not a science. You can have these evidence-based studies with hazard ratios, but maybe you have to throw all that out the door when you see this patient in front of you (where things don&rsquo;t apply). I think it&rsquo;s nice to have evidence, though, to have so many choices so that you can pick the right combination for the right patient.

Biochemical Relapse of Multiple Myeloma

For this patient, daratumumab/VD (bortezomib and dexamethasone) would be a very reasonable option because of her lenalidomide maintenance progression, and because she does have a known history of high-risk disease. Some practical considerations in treating with daratumumab/VD are, number 1, daratumumab is a relatively long infusion, so it&rsquo;s important to be prepared for that. What we can do, as physicians, is have the labs drawn ahead of time (perhaps the day before). We did that, routinely, on clinical trials. The good thing is, we don&rsquo;t really need a lot of labs to dose these drugs because daratumumab is not significantly affected by hepatic or renal function (although the label has only been studied to a clearance of 30 mL/min). Similarly, bortezomib physicians have a lot of experience with this.

But, some considerations include getting the labs drawn ahead of time; having the orders pre-signed (so it&rsquo;s not a last minute scramble); alerting the pharmacy and nursing staff that this is a first dose of daratumumab; having the patient arrive early so that everybody has that benefit of time; starting the infusion in a prompt fashion (with pharmacy having mixed the drug); giving those premedications, perhaps even at the same time that the pharmacy is instructed to mix the drug; and starting the drug early, not late in the day. And then, infusion-related reactions are common. It&rsquo;s 50%, but most of the time it&rsquo;s grade 1 or grade 2. It just means that we have to hold the drug, sometimes, and give additional pre-medications, rechallenge, and, potentially, re-escalate. But, all of that is only possible if you have time. If you&rsquo;re practicing in a busy community practice with a 9 to 5 schedule, and this patient doesn&rsquo;t start until 12, you&rsquo;re going to probably end up wasting a lot of drug. The patient won&rsquo;t get completed on their therapy.

Another strategy that, again, has been done in studies as well, now, is split-dose daratumumab. If you are a community center that&rsquo;s very pressed for time and you can&rsquo;t complete it in the first day, split it into 2 bags (8 mg/kilo on day 1 and day 2), that way you have the benefit of not wasting the drug if the patient has a significant reaction. And then, you can do the second dose on the next day. Those are very important, I think, practical considerations.

It&rsquo;s also important to remember, for those hospitals that may give daratumumab as an inpatient procedure, the drug is only stable for 15 hours. So, unlike other monoclonal antibodies that may be stable, longer (and we can sometimes just run it at a very low rate overnight), this drug could potentially expire depending on when it was hung. Then, there are 2 other practical considerations. One is the implication for blood banking. Daratumumab&rsquo;s target is CD38, which is primarily on myeloma cells but red cells also express CD38. We know, now, that if you give a patient daratumumab and you send a Type and Screen specimen to the bank, post-daratumumab, it will look (to them) that this patient has a lot of antibodies to a lot of antigens, because every red cell will be coated with daratumumab.

The way to deal with that is, number 1, in all of our chemotherapy template orders on the day 1 dosing, we put, &ldquo;Please send blood bank a specimen for type and screen.&rdquo; And, we inform them that this is a pre, first-dose daratumumab patient. That way, the blood bank is alert. In our center, for example, they do extended testingeither phenotyping or genotyping. That way, they know that when this patient comes back, even if the type and screen is raising these weird antibody questions, they know what the patient&rsquo;s blood type was, definitively, pre-daratumumab.

If somebody got daratumumab and that was not done, the other strategy is to use enzymes to strip away daratumumab from their red cells (using DTT [dithiothreitol] or trypsin). This makes the red cell naked again (without the daratumumab coating), and they can do their standard type and screen. The implication of that is certain antigens like Kell will also be stripped, so the blood bank will have to give Kell-negative blood as well. Blood banking is an important thing that physicians should know about, and patients should also know about it. They should have a card such that if they go to a local emergency room for perhaps trauma or a motor vehicle accident, the facility will also be aware of what&rsquo;s going on.

Luckily, even though this occurs, there&rsquo;s very little concern. We just published a paper revealing that there&rsquo;s really no hemolytic reactions or transfusion reactions. It&rsquo;s more of an artifact. And the biggest import of this is that you can delay transfusions in terms of finding the right product. The other practical implication of daratumumab (and I would broaden this to all of the monoclonal antibodies, whether it&rsquo;s daratumumab or elotuzumab), checkpoint inhibitors, and all of these antibodies, is that they are typically IgG (immunoglobulin G) kappa antibodies. Why is that important? Well, in myeloma, we test paraproteins to assess response. So, if you&rsquo;re making paraproteins for the myeloma, but are also giving exogenous antibody, how do you determine what is coming from what? Is it the patient or the antibody?

That can be difficult to determine. Luckily, in community practice, it probably won&rsquo;t make a big difference. The main implication of these interferences is going to be significant when patients should be reaching very low levels of disease where the M-spike is nearly gone and we&rsquo;re looking at either the difference between an M-spike of 0.1 and 0.2, or 0, or immunofixation-positive versus immunofixation-negative. At this low level of disease, it can be difficult to determine whether it&rsquo;s the exogenous antibody or the myeloma protein. This is, obviously, only applicable to IgG kappa patients. So, if it&rsquo;s an IgA (immunoglobulin A) lambda, and we know that if it&rsquo;s an IgG kappa being picked up, it&rsquo;s coming from the exogenous antibody.

One strategy that has developed is the daratumumab interference assay, where an anti-idiotypic antibody is added to the sample. And then, that moves daratumumab out of the way so you can see if there is any endogenous myeloma protein left. That hasn&rsquo;t yet been done with all of the antibodies, but it is important for community doctors to be aware of because, perhaps somebody who is in CR (complete response) is going to be called &ldquo;not in a CR,&rdquo; and it may just be a low-level interference?

The final important thing to think about for daratumumab/VD is, for both the proteasome inhibitors and for daratumumab, acyclovir or valacyclovir (for Shingles prophylaxis) is recommended. It&rsquo;s been known that proteasome inhibitors can reactivate Shingles in 20% of patients, and the Shingles vaccine, which is a live vaccine, is not yet recommended for hematologic malignancy. Therefore, prophylaxis is the way to go. It&rsquo;s also important to remember that these are renally cleared, so the dosing of those medications needs to be adjusted for renal dysfunction.

So, this is a patient who was diagnosed with symptomatic myeloma. She got RVD (bortezomib, lenalidomide, and dexamethasone) induction, transplant, and lenalidomide maintenance. And, fortunately, in spite of having a high-risk translocation t(14;16), her remission lasted 5 years. Luckily, we have many options to choose from at the time of relapse. Really, there&rsquo;s not a right answer, but the daratumumab/VD combination would be a great option and likely would give her a long remission duration.