This year’s American Society of Clinical Oncology (ASCO) annual meeting began last Friday and will run through tomorrow.

Multiple myeloma-related pre­sen­ta­tions have been taking place every day of the meeting. The main myeloma-related oral pre­sen­ta­tion session of the meeting, how­ever, took place on Friday. Research summarized during oral pre­sen­ta­tion sessions usually is par­tic­u­larly im­por­tant, either because the subject itself is im­por­tant, or because the results are based on sub­stan­tial amounts of evi­dence (for example, a sizable clin­i­cal trial).

Given the poten­tial importance of the re­search results pre­sented last Friday, The Beacon asked three myeloma specialists for their per­spec­tives on the pre­sen­ta­tions. The specialists who responded to several questions The Beacon asked them are:

• Dr. Francesca Gay of the University of Turin (Italy)
• Dr. Prashant Kapoor of the Mayo Clinic (Rochester, MN)
• Dr. Heather Landau of Memorial Sloan-Kettering (New York City).

As can be ex­pec­ted, Drs. Gay, Kapoor, and Landau did not have exactly the same impressions of the pre­sen­ta­tions they attended last Friday. However, there was some im­por­tant consistency in their feedback.

First, all three specialists felt the results that were pre­sented for the CAR T-cell ther­apy bb2121 were im­por­tant and, in many ways, impressive. There also was some disappointment, how­ever, with the results. Some of the specialists noted that even very deep re­sponses seen in some of the patients in the trial did not lead to remissions as long as they might have hoped.

Second, all three specialists noted the sig­nif­i­cance of results from a trial com­par­ing once-weekly Kyprolis (car­filz­o­mib) versus twice-weekly Kyprolis in re­lapsed myeloma patients. These results, the specialists said, could lead to sig­nif­i­cantly more use of the once-weekly dosing regi­men for Kyprolis in re­lapsed patients.

Quick Overview Of The Presentations

Before turning to the full details of the feedback the specialists shared with The Beacon, it is worth spending a few min­utes reviewing which pre­sen­ta­tions were given during Friday’s oral pre­sen­ta­tion session.

The session began with Dr. Maria-Victoria Mateos (University Hospital of Salamanca, Spain) summarizing results of the Phase 3 “ARROW” trial, which in­ves­ti­gated the use of once-weekly versus twice-weekly Kyprolis plus dexa­meth­a­sone in patients with re­lapsed and re­frac­tory mul­ti­ple myeloma (abstract #8000; presentation slides courtesy of Dr. Mateos).

Dr. Paul Richardson (Dana-Farber, Boston) followed on the agenda, presenting results of the Phase 3 OPTIMISMM trial (abstract #8001). The trial in­ves­ti­gated the use of Pomalyst (poma­lido­mide, Imnovid), Velcade (bor­tez­o­mib), and dexa­meth­a­sone (Decadron) com­pared to Velcade and dexa­meth­a­sone in re­lapsed or re­frac­tory mul­ti­ple myeloma patients who had pre­vi­ously been treated with Revlimid (lena­lido­mide).

Next, Dr. Ajai Chari (Mount Sinai, New York) shared results of a subgroup analysis of the MMY1001 trial, which in­ves­ti­gated the use of Darzalex (dara­tu­mu­mab) in com­bi­na­tion with Kyprolis and dexa­meth­a­sone in re­lapsed myeloma patients. The subgroup analysis focused on patients who were treated with, and stopped responding to, Revlimid (“Revlimid-refractory patients”) (abstract #8002).

Also during Friday’s oral session, Dr. Luciano Costa (University of Alabama at Birmingham) pre­sented results of a Phase 2 study of Venclexta (venetoclax) plus Kyprolis and dexa­meth­a­sone in patients with re­lapsed and re­frac­tory mul­ti­ple myeloma (abstract #8004; presentation slides [PDF] courtesy of Dr. Costa).

Dr. Costa’s pre­sen­ta­tion was followed by one given by Dr. James Berenson (Institute for Myeloma & Bone Cancer Research, Los Angeles), who summarized findings of a Phase 1 trial of Jakafi (ruxolitinib), Revlimid, and methylprednisolone in re­lapsed and re­frac­tory mul­ti­ple myeloma patients (abstract #8005).

The final three pre­sen­ta­tions of the session looked at stud­ies using immuno­therapy-based ap­proaches to treating myeloma.

Dr. Nina Shah (University of California, San Francisco) shared findings of a Phase 2 study that com­bined au­tol­o­gous (own) stem cell trans­plan­ta­tion with allo­geneic (donor) trans­plan­ta­tion of natural killer cells from umbilical cord blood (abstract #8006; presentation slides [PDF] courtesy of Dr. Shah).

In a much antic­i­pated pre­sen­ta­tion, Dr. Noopur Raje (Massachusetts General Hospital, Boston) summarized up­dated results of a Phase 1 trial of the anti-BCMA CAR T-cell ther­apy bb2121 in patients with re­lapsed and re­frac­tory mul­ti­ple myeloma (abstract #8007).

Finally, Dr. Aviva Krauss discussed results of a U.S. Food and Drug Admin­istra­tion analysis of Keytruda (pem­bro­lizu­mab) clin­i­cal trials in mul­ti­ple myeloma (abstract #8008). The analysis focused on immune-related adverse events seen during the trials.

Feedback From Drs. Gay, Kapoor, and Landau

Here are the questions The Beacon asked Drs. Gay, Kapoor, and Landau about Friday’s oral pre­sen­ta­tion session, accompanied by the re­sponses they provided.

Q. What do you feel were the key results pre­sented during the oral pre­sen­ta­tion session last Friday?

Dr. Prashant Kapoor:

The dose-escalation study involving BCMA-directed CAR T cells in re­lapsed/refractory mul­ti­ple myeloma shows that with a dose of at least 150 million cells, rapid and extremely deep re­sponses are feasible. All 16 patients who were in com­plete re­sponse were also found to be minimal residual dis­ease (MRD) neg­a­tive, the most desirable re­sponse category to achieve. Moreover, the pro­gres­sion-free sur­vival for the entire cohort was nearly 1 year, a remarkable im­prove­ment over historical data for such a heavily pre-treated pop­u­la­tion.

As such, the stars appear to be aligned for the ap­prov­al of CAR T-cell ther­apy once the results of the on­go­ing Phase 2 KarMMa study are released.

(All this having been said, there is also some disappointment related to the bb2121 results, as I describe later. In addi­tion, patients should be aware that par­tic­i­pa­tion in a trial involving a BCMA-directed ther­apy is likely to preclude them from sub­se­quently participating in other stud­ies using an anti-BCMA ap­proach – such as the GSK 205678 study of anti-BCMA con­ju­gated anti­body, or AMG 701 – re­gard­less of the level of BCMA ex­pres­sion on their myeloma cells.)

Dr. Francesca Gay

I think that with the in­creas­ing use of Revlimid up­front, one of the major issues in the near future will be the treat­ment of Revlimid-refractory patients at first relapse. Based on this con­sid­er­a­tion, I be­lieve that some of the key results pre­sented last Friday were the ones from the OPTIMISMM trial, showing the ef­fi­cacy of Pomalyst, Velcade, and dexa­meth­a­sone, and of the sub analysis of MM1001 in Revlimid-refractory patients (showing the ef­fec­tiveness of Darzalex, Kyprolis, and dexa­meth­a­sone).

Key results were also the results of the bb1212 study and of the [cord blood natural killer cell] study pre­sented by Dr. Nina Shah. I think these two stud­ies have very promising results. Very pre­lim­i­nary, but they explore novel treat­ment modalities that hopefully will in­crease the treat­ment armamentarium against mul­ti­ple myeloma in the near future.

Q. Were there results pre­sented during Friday’s session that par­tic­u­larly surprised you?

Dr. Landau:

That Kyprolis at 70 mg/m2 was very well-tolerated surprised me. Not to say that physicians should adopt this dosing until proven safe in the more commonly used Kyprolis, Revlimid, and dexa­meth­a­sone (KRD) regi­men, but with Darzalex this seems to be a well-tolerated and ef­fec­tive regi­men. We await more data to define the safety of this dosing with immuno­modu­la­tory agents [such as Revlimid and Pomalyst], but given that 56 mg/m2 twice weekly is safe, it is probably reason­able to use this dosing weekly.

Dr. Gay:

I was surprised by the results of the Phase 1 trial of Jakafi, Revlimid, and methylprednisolone, which showed the ef­fi­cacy of this com­bi­na­tion in patients re­frac­tory to Revlimid, in par­tic­u­lar because the dose of Revlimid admin­istered was lower than the dose cur­rently rec­om­mended at relapse.

Q. Were there results that disappointed you?

Dr. Landau:

I think the bluebird [bb212] data showing the less than 18 month pro­gres­sion-free sur­vival in patients who achieved com­plete re­sponse was a bit disappointing. Not to say that it shouldn’t be taken with a grain of salt, given the very ad­vanced patient pop­u­la­tion that was in­cluded in the study.  It just means that a single dose of this, which ef­fec­tively cytoreduces patients, at least in the mar­row, is not re­sult­ing in cures. However, if we compare the ef­fec­tively dosed patients to those who re­ceived lower doses, there is clear benefit. We just have a ways to go before we know how to use this tech­nology most ef­fec­tively.

Dr. Kapoor:

It is disappointing that despite attainment of such deep re­sponses [in the bb2121 study], the patients who had achieved MRD neg­a­tive state had a median pro­gres­sion-free sur­vival of only a year and a half.  If we take these numbers in the context of a recently pub­lished meta-analysis that showed the MRD-negative state to be asso­ci­ated with a median pro­gres­sion-free sur­vival of about 56 months, the enthusiasm for the CAR T-cell ap­proach is somewhat dampened, although it must be pointed out that unlike the current study pop­u­la­tion of heavily treated patients, the meta-analysis had only been conducted on a patient pop­u­la­tion with newly diag­nosed mul­ti­ple myeloma. The current study there­fore chal­lenges the dogma that MRD-negative state equates with exceedingly good prog­nosis, irrespective of how and when it is achieved.

Q. Were there any findings that may change your clin­i­cal prac­tice?

Dr. Gay:

Based on the results of the OPTIMISMM trial, as well as the results of the Darzalex, Kyprolis, and dexa­meth­a­sone Phase 3 study, these com­bi­na­tions will be avail­able outside of trials, and so in­crease the treat­ment op­tions for our patients.

Also, I think that based on the results of the ARROW trial, once weekly Kyprolis will be used in the treat­ment of relapsing patients more and more. There was no in­crease in toxicity, which is very im­por­tant, and the once weekly admin­istra­tion of course will be preferred by patients (so there is likely to be better compliance).

Dr. Kapoor:

The ARROW study has prac­tice-changing implications, allow­ing clinicians new insights into an old conundrum of dosing Kyprolis. The weekly schedule appears to not only be more con­ve­nient for the patients, but also yields higher and deeper re­sponses, translating into longer pro­gres­sion-free sur­vival.

Moreover, in the results pre­sented by Dr. Chari during Friday’s session, a 70 mg/m2 weekly dose could be safely integrated with Darzalex, sug­gesting that this dose would likely replace the 27 mg/m2 dose in com­bi­na­tions as well.  One cannot help but ask whether these results of ARROW with the 70 mg/m2 dose would have held up against a con­trol arm of 56 mg/m2 dose (the dose tested in ENDEAVOR trial).

Interestingly , another study, which compares the 27 mg/m2 dose to the 56 mg/m2 dose (SWOG S1304), and results of which were pre­sented at this morning’s poster session at ASCO, shows no pro­gres­sion-free sur­vival benefit with the higher dose (56 mg/m2) despite higher very good partial re­sponse (VGPR) rates with that dose, allow­ing some folks to extrapolate that the 70 mg/m2 weekly dose is likely superior to the 56 mg/m2 dose in re­lapsed / re­frac­tory mul­ti­ple myeloma.

Dr. Landau:

I think the only real prac­tice-changing results were the data sup­porting once weekly Kyprolis.  The schedule of Kyprolis is par­tic­u­larly onerous for patients.  While we need more data with other com­bi­na­tions, which are forthcoming, this rep­re­sents a more man­ageable way to de­liver a very ef­fec­tive drug.

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The Beacon’s initial ASCO 2018 article has more in­­for­ma­tion about the meeting, in­clud­ing how it is organized, and links to lists of oral pre­sen­ta­tions, education session pre­sen­ta­tions, and re­search posters. These lists are being up­dated reg­u­larly to in­clude links to pre­sen­ta­tion slide decks and posters that re­searchers are making avail­able to the Beacon’s readers.

Please note that, in their feedback to The Beacon, Drs. Gay, Kapoor, and Landau usually used generic names, such as “bortezomib” and “pomalidomide,” when referring to drugs, rather than brand names (such as “Velcade” and “Pomalyst”). This is a prac­tice common among re­searchers. The specialists’ feedback was edited, how­ever, to make use of brand names in those cases where brand names are more likely to be recog­nized by many Beacon readers.