The annual meetings of the American Society of Clinical Oncology (ASCO) and the Euro­pean He­ma­tol­ogy Asso­ci­a­tion (EHA) took place earlier this month. The two meetings were attended by tens of thousands of physi­cians from around the world, and featured a myriad of oral pre­sen­ta­tions, posters, and e-abstracts summarizing the re­­sults of new on­col­ogy- and he­ma­tol­ogy-related re­search.

Included in the re­search pre­sented at the two meetings were more than 200 stud­ies discussing new mul­ti­ple myeloma-related findings.

In addi­tion to the two large meetings held earlier this month, the Inter­na­tion­al Myeloma Work­ing Group (IMWG) held its 2015 annual summit after the ASCO meeting and im­medi­ately prior to the EHA meeting. The summit is an im­por­tant oppor­tu­ni­ty each year for lead­ing myeloma re­searchers to discuss key issues in the field, con­sider ways to col­lab­o­rate more closely, and plan new clin­i­cal trials and laboratory stud­ies.

The Beacon will be continuing in the next couple weeks with its coverage of the re­search pre­sented at the ASCO and EHA meetings.

In the meantime, to help its readers get a sense of what myeloma-related re­search pre­sented and discussed at these meetings was par­tic­u­larly im­por­tant, The Beacon reached out to myeloma spe­cialist Dr. Ola Landgren. Dr. Landgren is Chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York City. Prior to joining Sloan Kettering last year, Dr. Landgren had been Chief of the Multiple Myeloma Section at the National Cancer In­sti­tute in Bethesda, Maryland.

In an interview with Beacon founder and pub­lisher Boris Simkovich, Dr. Landgren shared his thoughts about the key myeloma-related re­search pre­sented at the ASCO, EHA, and IMWG meetings this month. The inter­view can be found below, and it is followed by links to re­lated abstracts, slide decks, and posters from the ASCO and EHA meetings.

Boris Simkovich: Let’s start our dis­cus­sion by focusing on the ASCO and EHA meetings. Which myeloma re­search re­­sults pre­sented at the two meetings do you feel were the most sig­nif­i­cant?

Dr. Landgren: I think there were sev­er­al ex­cit­ing new myeloma-related devel­op­ments. Some of the key re­sults in­cluded:

Phase 3 data for elotuzumab – Elotuzumab ^[1] in com­bi­na­tion with Revlimid (lena­lido­mide) and dexa­meth­a­sone (Decadron), versus Revlimid ^[2] and dexamethasone ^[3] alone, showed a sig­nif­i­cant and clin­i­cally meaningful im­prove­ment in pro­gres­sion-free sur­vival. We have a new class of myeloma drugs.

More data about the CD38 mono­clonal anti­bodies – These po­ten­tial new myeloma ther­a­pies in­clude dara­tu­mumab ^[4], SAR650984 ^[5], and MOR202 ^[6]. Their data look promising. Even in heavily pre­treated re­lapsed myeloma patients, this class of drugs de­livers strong re­­sults as single-agent ther­apy. There were also some data sug­gesting that immuno­modu­la­tory agents (IMiDs) such as Revlimid and Pomalyst ^[7] (poma­lido­mide, Imnovid) may in­crease the amount of CD38 found on the surface of myeloma cells. That will be in­ter­est­ing to explore fur­ther in com­bi­na­tion ther­apy ap­proaches.

Updated and new data about Kyprolis – The ASPIRE trial re­­sults were up­dated and showed impressive long pro­gres­sion-free sur­vival for Kyprolis ^[8] (car­filz­o­mib), Revlimid, and dexa­meth­a­sone (KRd) in re­lapsed mye­lo­ma. Also, there were new re­­sults from the ENDEAVOR study com­par­ing Kyprolis and dexa­meth­a­sone versus Velcade (bor­tez­o­mib) and dexa­meth­a­sone in re­lapsed myeloma. They showed sig­nif­i­cantly deeper and longer re­sponses for Kyprolis / dexa­meth­a­sone. Another study showed that KRd treat­ment deep­ened re­sponses after initial KRd ther­apy followed by high-dose mel­phalan and stem cell trans­plan­ta­tion.

New insights into dis­ease biology – A molecular study used whole exome sequencing and SNP arrays in both mono­clonal gam­mop­athy of undetermined sig­nif­i­cance (MGUS) and myeloma. It showed that MGUS is highly ge­net­ic­ally ab­nor­mal. Perhaps the devel­op­ment of myeloma after MGUS is due to alterations on sur­rounding cells in the bone mar­row, rather than changes directly in the plasma cells? Future stud­ies will tell us more.

Several other stud­ies were pre­sented. These are the ones I would emphasize as being par­tic­u­larly im­por­tant.

Going back to the elotuzumab re­­sults for a bit. The pro­gres­sion-free sur­vival seen for the elo­tuzu­mab-Revlimid-dexamethasone com­bi­na­tion was superior to that seen for Revlimid and dexa­meth­a­sone alone. However, the sur­vival seen with the three-drug com­bi­na­tion in the re­­sults pre­sented at ASCO and EHA wasn’t as sub­stan­tial as had been seen in an earlier Phase 2 study testing the com­bi­na­tion in a similar group of patients.

How is that affecting how you and other myeloma spe­cialists are seeing the elotuzumab re­­sults? Is there any disappointment? Or do you feel that it’s just really im­por­tant that we now have a com­par­a­tive trial showing a clear ben­e­fit to combining elotuzumab with Revlimid and dexa­meth­a­sone?

Every study is dif­fer­en­t. Comparisons across stud­ies have to be done with caution, since patients may be dif­fer­en­t in terms of dis­ease biology, comorbidities, etc. Also, single-center Phase 2 trials have the po­ten­tial to be biased, for example, if the center is very good at taking care of and managing patients with a given dis­ease.

Therefore, the gold standard for drug devel­op­ment has mul­ti­ple steps when it comes to dif­fer­en­t phases for trials: Phase 1 to define the optimal dose in rela­tion­ to safety; Phase 2 to assess if there is a signal sup­port­ive of effect; and ran­domized Phase 3 to compare the new ther­apy to an estab­lished ther­apy (which serves as a con­trol). This is standard.

With regards to elotuzumab, the ran­domized Phase 3 study showed sig­nif­i­cant and clin­i­cally meaningful pro­gres­sion-free sur­vival ben­e­fits when com­par­ing elotuzumab + Revlimid / dexa­meth­a­sone versus Revlimid / dexa­meth­a­sone. I think the re­­sults are solid.

In myeloma, we do not yet have an estab­lished curative ther­apy to offer our patients. Clearly, elotuzumab adds to what we already have (Revlimid / dexa­meth­a­sone). This is im­por­tant for patients who have re­lapsed myeloma and need ther­apy. As doctors, we need many op­tions to choose be­tween.

I think the data for elotuzumab are solid and they sup­port the fact that elotuzumab could be another op­tion.

Regarding the CD38 mono­clonal anti­body ther­a­pies, was there any­thing in the latest dara­tu­mu­mab re­­sults that surprised you? Also, the two recent meetings gave some initial glimpses into the po­ten­tial ef­fec­tiveness of MOR202, another CD38 mono­clonal anti­body. What are your impressions of the drug so far based on those glimpses – does it look like it will have the same level of anti-myeloma ac­­tiv­ity that’s been seen, for example, in dara­tu­mu­mab?

There was nothing that neg­a­tively surprised me re­gard­ing dara­tu­mu­mab. Studies keep showing impressive re­­sults.

MOR202 looks in­ter­est­ing as well. So far, we have seen data about dosing and toxicity. It is too early to com­ment on the im­pact of this drug in patients and to speculate if there is a dif­fer­ence or not be­tween dara­tu­mu­mab and MOR202. We need more data!

I thought the abstract looking at the im­pact of immuno­modu­la­tory agents (IMiDs) on how much CD38 is found on the surface of plasma cells was an in­ter­est­ing study. Is there a clin­i­cal ben­e­fit when using IMiDs and CD38 mono­clonal anti­bodies to­geth­er? This needs to be assessed for all CD38 mono­clonal anti­bodies.

Can we talk a bit more about the findings re­lated to MGUS and myeloma based on detailed ge­netic analyses? You mentioned that the study found that MGUS is “highly ge­net­ic­ally ab­nor­mal”.  Can you describe a bit more what you mean by this, and why it leads you to wonder, for example, if “the devel­op­ment of myeloma after MGUS [might be] due to alterations on surrounding cells in the bone mar­row”?

The study by Gareth Morgan's group in­cluded both whole exome sequencing and SNP array assays. It ex­amined MGUS as well as myeloma samples.  (Editor’s note: “Whole exome sequencing” de­ter­mines the com­plete sequence of DNA mol­e­cules in a cell’s genes; “SNP array assays” are tests to de­ter­mine if a cell’s genes have pre-specified DNA sequences at spe­cif­ic locations on the genes.)

Early last year, a study ^[9] pub­lished in the journal Cancer Cell reported re­­sults of whole exome sequencing of over 200 myeloma cell samples. The re­searchers found massive ge­netic heterogeneity, sug­gesting that every newly diag­nosed myeloma patient has 5 to 10 (or more) parallel myelomas going on at the same time. These parallel myelomas have dif­fer­en­t susceptibilities to a given ther­apy. Some respond well, others don't.

Coming back to the new study by Morgan and his colleagues that was pre­sented at the EHA meeting, it shows that MGUS has ge­netic heterogeneity similar to what was seen in myeloma in the study pub­lished last year. The EHA study is the first that has done this type of analysis in MGUS.

Generally, we need more than one study showing some­thing before we can conclude some­thing definitive. This study sug­gests that the trans­formation from MGUS to myeloma is not due to a single ge­netic ab­nor­mal­i­ty. In fact, because the cells are massively ge­net­ic­ally ab­nor­mal already during MGUS, it raises the possibility that there is some­thing outside the tumor cells that con­trols their destiny. Maybe surrounding cells in the bone mar­row pro­duce factors that hold MGUS cells back from pro­gres­sion. Maybe there are factors that all of a sudden are pro­duced and stim­u­late the MGUS cells to be­come symp­tomatic myeloma. Maybe there are other mech­a­nisms, or a range or com­bi­na­tion of mech­a­nisms.

Based on these new data, we need rep­li­ca­tion. If rep­li­cated, future stud­ies will have to keep an eye on non-tumor cells as well. This is novel in­­for­ma­tion hot off the press. Dr. Morgan has a lot of good ideas and data about the biology of mul­ti­ple myeloma. I respect him very much. We are devel­op­ing new col­lab­o­rations as we speak.

Two issues that are cur­rently of great interest to myeloma patients are the role of trans­plan­ta­tion in initial ther­a­py for newly diag­nosed patients, and the role of main­te­nance ther­apy after initial ther­a­py. Were there any new re­­sults at the ASCO or EHA meetings that you feel could affect de­ci­sions on these issues?

There was no new in­­for­ma­tion guiding us in new directions re­gard­ing these two topics.

However, looking at the big picture, I think it is fair to say that the field over­all is moving in the direction of con­tin­uous ther­apy (maintenance) to prevent relapse.

Also, I think it is fair to say that there is a move­ment to­wards targeting deeper re­sponses, in­clud­ing minimal residual dis­ease (MRD) neg­a­tive status, with the use of newer drugs. This is true both in newly diag­nosed and in re­lapsed patients, and it is raising interest in the use of four-drug com­bi­na­tions, such as the Kyprolis, Revlimid, cyclo­phos­pha­mide, and dexa­meth­a­sone regi­men, for which early re­­sults from the UK Myeloma XI trial were pre­sented at the EHA meeting.

The move­ment to­ward targeting deeper re­sponses fur­ther emphasizes, in turn, the need to better define the future role of au­tol­o­gous trans­plan­ta­tion in myeloma – early versus delayed, and for whom? Small pieces in many of the stud­ies pre­sented at the ASCO and EHA meetings con­firm that these im­por­tant questions are on the table.

The 2015 annual summit of the Inter­na­tional Myeloma Work­ing Group took place in Vienna be­tween the ASCO and EHA meetings. As you look back on this year’s summit, what dis­cus­sions and de­ci­sions that may have been made during the meeting do you think will have the greatest im­pact with­in the myeloma com­munity in the next sev­er­al years?

There were many dis­cus­sions during the Summit. From my perspective, I think the key topics were:

Molecular profiling – We are learning more and more about how the “molecular profile” of a patient’s dis­ease – its detailed ge­netics and bio­­markers – affects how the dis­ease responds to treat­ment. And, at the summit, we discussed sev­er­al im­por­tant questions re­lated to this topic: What should be the role of molecular pro­fil­ing? When should it be done … and how?

I think the conclusion was that there are many new tech­nolo­gies for molecular pro­fil­ing that are either avail­able now, or that will be avail­able in the very near future. I also think the consensus was that banking bone mar­row samples is the way to go for new trials. Discussions and de­ci­sions about which profiling assays are best will oc­cur in the near future. More dis­cus­sion is needed.

Study designs – As more new myeloma drugs get approved, it be­comes harder for drugs still under devel­op­ment to statistically prove they provide an over­all sur­vival ben­e­fit. Many regu­la­tory author­i­ties around the world, how­ever, re­quire statistical proof of an over­all sur­vival ben­e­fit before they will approve a new myeloma drug. So we need strategies to move things for­ward. There were dis­cus­sions on how such strategies should be devel­oped and how trials can be de­signed to reflect those strategies. This is im­por­tant, as it serves to secure the pipe­line of new drugs being devel­oped for myeloma. Until we have devel­oped an estab­lished cure for myeloma, we will need new drugs.

Minimal residual dis­ease – This topic was up for dis­cus­sion once again. It was clear that everybody wants MRD to be in­cluded as an end­point in the re­sponse criteria used, for example, during clin­i­cal trials. The dis­cus­sions during the Summit focused on how to implement this goal.

There seem to be two schools of thought on this issue.  One is that MRD should be defined based on a spe­cif­ic test, i.e., “With Method X, MRD negativity is fulfilled." The other is that MRD should be defined based on sensitivity, i.e., “With method X – or with other methods proven to have equal or better sensitivity – MRD negativity is fulfilled."

I agree that it is im­por­tant to have a method as a reference. In my opinion, how­ever, we need to always work to make things better. Until we have a test that guar­an­tees a cure, we need to work hard and de­vel­op new and better tests. Therefore, I favor the sensitivity solu­tion. It will allow us all to de­vel­op new strategies.

Drug costs – With more and better drugs, the cost of treat­ment is becoming an even hotter topic. New drugs are expensive. How do we de­ter­mine which drugs are the best, and how do we justify – fi­nan­cially – com­bin­ing an expensive new ther­apy with other drugs?

This will be a hard nut to crack. Will stringing out expensive drugs and giving them sequentially be the way to go? Or will it be better to com­bine them and give them all to­geth­er?  Or both? Or neither? More dis­cus­sion on these questions will be needed for sure.

Novel drug classes – There also was dis­cus­sion during the summit about novel classes of myeloma drugs. By that I mean drugs in classes dif­fer­en­t from those you find when you look at either estab­lished myeloma ther­a­pies, or myeloma ther­a­pies in the near-term devel­op­ment pipe­line.

We talked, for example, about checkpoint in­hib­i­tors, alone and in com­bi­na­tion with immuno­modu­la­tory agents (IMiDs). There also was dis­cus­sion about selinexor, a nuclear export in­hib­i­tor; CAR T-cell ther­apy ^[10], which is in early clin­i­cal devel­op­ment for myeloma (we may have a new strat­e­gy here); and about a new 19S pro­te­a­some in­hib­i­tor.

There were other drugs discussed as well. The bottom line is that there are many new drugs being de­vel­oped as we speak. It looks very promising.

Thank you for being so generous with your time and sharing with the Beacon’s readers your thoughts about the recent meetings. Your perspectives are always very helpful and very much ap­pre­ci­ated.

Thank you for having me. I'm very happy to share perspectives and to make sure patients get access to new, im­por­tant in­­for­ma­tion. The myeloma field is moving for­ward faster than ever. Every 6 months there is new in­­for­ma­tion that has clin­i­cal implications. It is an ex­cit­ing time with a stream of new and better treat­ment op­tions. The future looks very bright!

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Related Abstracts, Slide Decks, Posters, And Other Links

Elotuzumab – ASCO abstract ^[11] 8508 and re­lated slide deck ^[12] courtesy of Dr. Sagar Lonial; EHA abstract ^[13] S471; re­lated journal article ^[14]; ASCO 2013 abstract ^[15] 8542 with re­­sults of similar Phase 1/2 study and re­lated poster ^[16] courtesy of Dr. Lonial.

Daratumumab – ASCO abstract ^[17] LB8512 and re­lated slide deck ^[18] courtesy of Dr. Lonial; EHA abstract ^[19] S430.

MOR202 – ASCO abstract ^[20] 8574 and re­lated poster ^[21] courtesy of Dr. Marc Raab; EHA abstract ^[22] S789.

Immunomodulatory agents and CD38 – ASCO abstract ^[23] 8588; EHA abstract ^[24] P636.

Kyprolis (ASPIRE) – ASCO abstract ^[25] 8525; EHA abstract ^[26] S427.

Kyprolis (ENDEAVOR) – ASCO abstract ^[27] 8509; EHA abstract ^[28] LB2071.

MGUS and mul­ti­ple myeloma ge­netics – EHA abstract ^[29] S476 and re­lated slide deck ^[30] courtesy of Ms. Aneta Mikulasova.

Kyprolis, cyclo­phos­pha­mide, Revlimid, and dexa­meth­a­sone – EHA abstract ^[31] S428.