Ajai Chari, MD: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’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 ratesparticularly 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’s important to remember that when this study was designed, bortezomib was being given intravenously, twice weekly. We know that’s not as well tolerated as subcutaneous therapy, because we know that the toxicity of bortezomib is related to Cmax, and not in the area under the curve. So, by giving it subcutaneously, we know that you can get comparable efficacy without that high Cmaxso, 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’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 responsesboth 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 roleprobably 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’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’t significantly increase responses, but did result in increased neutropenia. So, it doesn’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’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’ll have to see how these regimens pan out in the future.
Transcript edited for clarity.
Biochemical Progression of Stage II Myeloma