BCMA Day: At ASH ‘18, Cell Therapies For Myeloma Take Center Stage

Xconomy National — 

The treatment landscape for multiple myeloma, a deadly cancer of the bone marrow that affects about 30,000 Americans every year, has changed significantly over the past decade. And more changes look to be on the way.

Take the results of a Phase 3 study just reported today at the American Society of Hematology’s (ASH) yearly meeting in San Diego. In the study, a combination of the Johnson & Johnson (NYSE: JNJ) drug daratumumab (Darzalex) and staple multiple myeloma drugs lenalidomide (Revlimid) and dexamethasone (an immune-suppressing steroid) cut the risk of death for newly diagnosed patients who aren’t eligible for bone marrow transplants by 44 percent. The so-called D-Rd regimen could be “the new standard of care” for these patients, lead investigator Thierry Facon of Hôpital Claude Huriez said, according to OncLive. J&J plans to file for FDA approval in the future.

But the tricky thing with multiple myeloma is its persistence. Most everyone relapses. That means despite the availability of newer drugs and combinations that can put patients into remission for longer periods of time, opportunities still remain for drugmakers to work their way into the treatment paradigm.

Enter the newest weapon against multiple myeloma: drugs that target BCMA, or B-cell maturation antigen. As Xconomy detailed in its ASH preview last week, several groups are developing CAR-T cell therapies to seek out cancer cells that make BCMA and obliterate them. The results so far, in patients who have failed several treatments, have been promising. Yet several questions hang over these treatments. How long will they last? Will they ever be safe enough to be useful as more than just a last ditch effort for people who have run out of options? Will their place be usurped by an emerging group of antibody drugs that also target BCMA?

It’ll take time to answer those questions, but one thing is clear at this point: biopharma is heavily invested in BCMA, and the field is getting more and more competitive by the day. At ASH, cell therapies from Bluebird Bio (NASDAQ: BLUE) and partner Celgene (NASDAQ: CELG), Nanjing Legend Biotech and partner J&J, and Poseida Therapeutics, among others, were all on display, along with a BCMA-targeting antibody from Amgen (NASDAQ: AMGN).

It’s impressive “how many companies, centers and investigators have jumped onto the BCMA bandwagon, and as a result, how crowded this space is becoming already,” wrote Leerink analyst Geoffrey Porges, after attending a swath of BCMA presentations at ASH.

Here’s a snapshot of the BCMA programs companies presented at ASH, and where they stand as of now.

Bluebird Bio/Celgene

Bluebird and Celgene are out in front with an experimental program called bb2121; they’ve finished enrolling patients in a pivotal study (the last before an approval application) called KarMMA, and aim to file for approval in 2020. Bb2121 “retains a sizeable lead” over its rivals, wrote Leerink analyst Mani Foroohar. The question is whether Bluebird and Celgene can maintain that lead with fierce competition closing in. (Privately held Poseida Therapeutics, for instance, may not be that far behind. More on that below.)

There were no bb2121 updates at ASH. Instead, Celgene’s multi-pronged BCMA strategy came into focus. Celgene has rights to bb2121, as well as a follow-on program with Bluebird, bb21217, that is meant to produce better, longer lasting results. Celgene also has a third BCMA CAR-T program in development, JCARH125, that it acquired when it bought Juno Therapeutics. The first glimpses of both were presented at ASH.

BB21217: After a median of 5.9 months, 10 of 12 patients (83 percent) who failed a median of 7 therapies responded to bb21217; three of them had no trace of cancer. One of those 10 patients relapsed after four months. Another had a serious case of what’s known as “cytokine release syndrome,” or CRS, a common and potentially lethal CAR-T side effect.

JCARH125: After a median of 11 weeks, 36 of 44 (82 percent) of patients who failed a median of 7 therapies responded to JCARH125, and 43 percent of them saw their disease go into remission. Four of the 44 patients had a serious CRS case.

Nanjing Legend/Johnson & Johnson

J&J, whose drug daratumumab is becoming more and more entrenched as a staple multiple myeloma drug, paid up big to get involved in the BCMA race. In December 2017, it paid China’s Nanjing Legend $350 million up front for rights to LCAR-B38M, after Phase 1 data that turned heads at the American Society of Clinical Oncology’s annual meeting in 2017. ASH represented the first significant update from the program since then.

The data surrounding LCAR-B38M, however, are “controversial, to say the least,” wrote Leerink analyst Porges. Since reporting a 95 percent response rate at ASCO, the data have been criticized for “selective patient disclosures by treatment site.” At ASH, for instance, Nanjing reported data from 57 patients at a trial site in Xian, China. Additionally, noted Porges, Nanjing appears to have selected patients who aren’t as sick as those in Celgene’s studies—they failed a median of three treatments. Taken together, “the data…appear very good, although attempting to compare this data to the CAR-T trials by Celgene is a flawed exercise,” wrote Porges.

Nonetheless, this is a short summary what Nanjing Legend and J&J reported:

LCAR-B38M: After a median follow-up of 12 months, 50 of 57 (88 percent) of patients had responded to treatment, of which 42 (74 percent) showed no signs of cancer. The treatment has lasted a median of 16 months. Four patients (7 percent) had a severe CRS case.


Amgen is coming at multiple myeloma from a different angle. It’s using an antibody called AMG 420 that latches on to two different targets: BCMA and a second that is on T cells. The goal is to provide a simpler alternative to CAR-T. Amgen isn’t alone with this approach—others, like GlaxoSmithKline, are involved too—but it is the first to produce human data. Perhaps Amgen “may be clever enough to differentiate from the pack with an ‘off-the-shelf’ anti-BCMA product,” Porges wrote, which might be suitable for older patients in the community setting who can’t get access to, or aren’t eligible for, CAR-T. It might have to: the results “fall short” of the recent hype that’s surrounded the program, Porges wrote.

Even so, should AMG 420 succeed in clinical testing and get to market, Amgen will have its own logistical hurdles to overcome. One dose cycle of AMG 420 requires a continuous IV infusion for four weeks straight, then two weeks off, and patients need to keep getting the drug via a permanent catheter or port delivery system to see its effects. That “may have contributed to the rates of serious infection [12 patients (29 percent)]” that Amgen has seen in the study, Porges wrote.

AMG 420: Amgen tested multiple doses. 13 of 42 patients (31 percent) who had failed a median of four treatments responded to AMG420, though Amgen highlighted that 7 of 10 (70 percent) responded to the dose it intends to take into further testing.

Poseida Therapeutics

Poseida, a privately held company based in San Diego, CA, is pursuing an aggressive development timeline for its CAR-T product, a treatment called P-BCMA-101, for which it owns full rights. Poseida aims to begin a pivotal study next year and file for approval by the end of 2020, which would put it right in the thick of the race with Bluebird/Celgene, Nanjing/J&J and others. At ASH, Poseida disclosed the most detailed data to date on P-BCMA 101. Here’s a snapshot:

P-BCMA-101: 15 of 19 evaluable patients who failed at least six treatments responded to its experimental P-BCMA-101, and five of them had no trace of cancer. It’s unclear how long those responses have lasted. Poseida noted that four of four responded to the mid-range dose it will take into Phase 2 studies. Poseida hasn’t seen any serious cases of CRS in the study yet.