Joshua Richter, MD

New Directions in Newly Diagnosed Multiple Myeloma

Question

How has the treatment landscape for newly diagnosed multiple myeloma evolved over the years and what do you feel are the most promising approaches on the horizon in this setting?

Answer

This is a big question. The big evolution in newly diagnosed multiple myeloma really has been the establishment of triplets as the mainstay of therapy. If you look across a variety of studies in transplant-eligible and transplant-ineligible patients, triplets are really ruling the roost. The really big changes we are looking at now is not going from 2 to 3 drugs, but from going from 3 to 4 drugs.

This was looked at way back when in the EVOLUTION Trial (ClinicalTrials.gov Identifier: NCT00507442).¹ It included bortezomib, cyclophosphamide, lenalidomide, and dexamethasone, and it used different combinations and there were no clear improvements in that case in adding a fourth drug. Now, we have monoclonal antibodies such as daratumumab, isatuximab, and elotuzumab, and the toxicity profile is such that we are starting to see real benefits of 4 drugs over 3. We saw this in the ALCYONE trial (ClinicalTrials.gov Identifier: NCT02195479)² and the CASSIOPEIA Trial (ClinicalTrials.gov Identifier: NCT02541383)³ and we are anxiously anticipating the latest results from the GRIFFIN Trial (ClinicalTrials.gov Identifier: NCT02874742) to see what type of impact that it is going to make.

There is always this big discussion in newly diagnosed patients about the decision of: Is the patient transplant eligible or transplant ineligible? There is a thought that if you get a deep enough remission upfront and you get [minimal residual disease]-negative, maybe you don’t need that transplant. With some of these quadruplet therapies, across the board people are getting 40% to 50% or even higher rates of [minimal residual disease]-negativity. So, if we start to get to the point where the modern-day drugs get you so deep [into remission] that it doesn’t matter and nobody needs a transplant, that’s an interesting thing. I still think transplant plays a major in the management of upfront myeloma.

Question

The ANDROMEDA study recently met its primary endpoint of more than 50% of patients with hematologic complete response to subcutaneous daratumumab in newly diagnosed amyloid light-chain (AL) amyloidosis. In your view, what could be the biggest advantages of subcutaneous drug delivery over other methods?

Answer

The ANDROMEDA study (ClinicalTrials.gov Identifier: NCT03201965) was really groundbreaking for amyloid. We’ve known for years that the standard for most patients with amyloid has been cyclophosphamide, bortezomib and dexamethasone (CyBorD), but still some older patients get melphalan and dexamethasone for the transplant ineligible. However, CyBorD has been really standard. Then, comes the question of giving daratumumab along with CyBorD and obviously in every regimen that we have studied, people have done better with daratumumab than not across the board when you look at the studies.

So, the question is: Does this help upfront amyloid patients? I love this study because I take care of a lot of amyloid patients and a lot of them, when they present, already have significant organ dysfunction. It may be cardiac or renal. One of the issues that I have had with giving daratumumab upfront to these patients is the volume. The first dose is in a liter and the second dose is in 500 ccs. For patients with severe cardiac and renal compromise, this can be a problem. It can be a really big issue because when you are trying to treat the underlying cause, you can affect their fluid issues.

The ability now to give this subcutaneously is going to change the landscape of amyloid. It means that for patients with amyloid we don’t have to worry about giving them a liter or a half a liter of fluid. So, to me this allows us to incorporate the extra drugs and with ANDROMEDA⁴ they not only had an overall hematologic responses of 96%, which is amazing, but here they had an organ response of 64%. The organ response rate is generally not that good. So, we are able to get fast reduction in light chain levels and deep reductions in light chain levels and hopefully in these frail patients get them their organ function back.

Question

Please discuss the results of the DREAMM-9 phase 3 study examining the addition of belantamab mafodotin to bortezomib, lenalidomide, and dexamethasone (VRd) compared with VRd alone in transplant-ineligible newly diagnosed multiple myeloma. What would be some likely pros and cons of treatment with this antibody-drug conjugate, in your view?

Answer

We don’t have results yet. DREAMM-9 (ClinicalTrials.gov Identifier: NCT04091126)⁵ is going to answer some very important questions. The biggest question is the way we give a lot of our drugs. The way we give them now is not biological, but we give them in chronological order ([lenolidomide] then pomalidomide, [bortezomib] then [carfilzomib]). Now, we have more targeted immunologic agents targeting CD38 and with belantamab mafodotin we will have BCMA (B-cell maturation antigen). The question is, [is it] CD38 then BCMA, or BCMA first?

This trial is going to help answer whether to move BCMAs all the way to the frontline. We won’t be able to compare trial to trial. So, it is not that we can compare this to GRIFFIN. However, at some levels we are going to say patients who got VRd vs monoclonal [antibody] plus VRd and ask what do the rates look like and what do the toxicity rates look like? So, to me, this is really very forward thinking about where do BCMA therapies fit. With the activity that we have seen with belantamab mafodotin in heavily refractory patients, I am really excited to see how it is going to augment things early on.

Question

According to research presented during the ASCO20 Virtual Scientific Program (ClinicalTrials.gov Identifier: NCT01081028),⁶ and based on real-world results from a study on patients with newly diagnosed disease who were in the Connect MM Registry, patients with renal impairment should now be considered for inclusion in clinical trials, as well as for treatment with lenalidomide-bortezomib-dexamethasone (RVd). Do you agree with this assessment? Why or why not?

Answer

This has been one of the difficult things about clinical trials in myeloma and their applicability post approval. Many patients with myeloma in some course of their therapy either at presentation or later on will go on to develop renal insufficiency. So, those patients are excluded from key clinical trials because of the way the trials are designed. First of all, we don’t get the answer of how the drugs work in terms of efficacy and toxicity in that group, and then after the drug’s approval, we are doing [our] best guesswork to try to give these drugs to these real-life patients with renal dysfunction.

So, I think this is a great step forward and over time, we really need to embrace not just the healthiest of healthy patients in the clinical trials, but those who are sick. This is really a great step forward to be able to take information from clinical trials and apply it to patients at the bedside. The other thing that I think is great in general about this trial is that a lot of patients, when diagnosed with myeloma and renal failure, are treated with CyBorD over RVd because of concerns about Revlimid and renal issues. I think this can be viewed differently and it really shows that Revlimid can be given regardless of renal function. There is a dose for it. We have had a large number of studies showing that Revlimid-containing regimens are better than cytotoxic upfront both in the IFM-MP2013 trial (ClinicalTrials.gov Identifier: NCT01564537 and at EudraCT as 2013-003174-27)⁷ and the FORTE trial (ClinicalTrials.gov Identifier: NCT02203643).⁸

So it really enforces that patients can get VRd, which is still the standard not just for transplant-eligible or -ineligible patients, old or young, but for renal impairment as well. We need to know how to apply all these therapies in all our patients, especially those with renal impairment.

Question

Are there any other recent study results or data that you feel are of particular interest in the setting of newly diagnosed multiple myeloma?

Answer

We generally walk in with a lot of high hopes in patients with newly diagnosed myeloma because of all the drugs we have and the huge pipeline. But one of the things that has really been an issue has been high-risk myeloma patients, because we are confident we can get them into remission, but we are not confident that we can keep them in remission.

This year, I was the discussant for ASCO’s high-risk section and all the 3 abstracts that I discussed were focusing around high-risk disease in the newly diagnosed [setting] and how to attack that. The 3 abstracts were: “Primary analysis of the randomized phase 2 trial of bortezomib, lenalidomide, dexamethasone with/without elotuzumab for newly diagnosed, high-risk multiple myeloma (SWOG-1211)”;⁹ “Long-term follow-up of BMT CTN 0702 (STaMINA) of postautologous hematopoietic cell transplantation (autoHCT) strategies in the upfront treatment of multiple myeloma (MM)”;¹⁰ and “Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: Interim analysis of the GMMG-CONCEPT trial”.¹¹

All 3 of these were really looking for approaches to overcome high-risk disease in newly diagnosed patients. The STAMINA trial looked at no transplant vs single vs tandem, and it looked actually like tandem auto would be of [progression-free survival] benefit in patients with high-risk disease. So, I think that transplant is not dead, but there are still some people out there who need 2 of them; maybe the high-risk patients. The other 2 trials really looked at taking a triplet and turning it into a quad with a monoclonal antibody to offset high-risk disease. If you go from a doublet to a triplet by using daratumumab, such as Rd to DRd or Vd to DVd, there is probably some improvement in high-risk disease by adding the daratumumab. But when we go from triplets to quadruplets with daratumumab for example, VRd to dara-RVd and VTd to dara-VTd, so far we have not seen improvements in patients with high-risk disease. But for some of these quads, there may be some promise to offset high-risk disease, such as with Isa-KRd [isatuximab, carfilzomib, lenalidomide, and dexamethasone], and Elo-RVd [elotuzumab plus bortezomib, lenalidomide, and dexamethasone].

There is reason for optimism. Now more than ever, it would not surprise me if we didn’t [already] have the tools to cure some patients at our disposal now, but we just need to know how to use them optimally to achieve that.