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Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts from the ‘Multiple Myeloma’ category

Much of the focus in multiple myeloma over the last decade has focused on two key drug classes – proteasome inhibitors and IMiDs – with some recent approvals for monoclonal antibodies targeting key proteins on the surface of malignant myeloma cells such as CD38.

#ASH16 in San Diego

Combinations of these core therapies have lead to a noticeable improvement in outcomes for people living with the disease – from 3-4 years over a decade ago to now approaching 10 years post diagnosis.

If we want to continuously beat the status quo and improve on the chronicity, however, it is likely that several things will need to happen:

  • Better understand mechanisms of resistance that induce relapse
  • Develop predictive biomarkers of response
  • Identify novel therapeutic targets

Here. we focus on the latest preclinical findings that were recently presented at the American Society of Hematology (ASH) in San Diego and explore where the future might be headed in this disease.

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Jounce Poster AACR 2016

The AACR Poster Halls get packed quickly!

It’s time to change direction and take a look at some of the Gems from the Poster Halls at the recent American Association for Cancer Research (AACR) meeting.

One particular abstract that looked interesting related to the Aduro compound, BION–1301, which is a monoclonal antibody targeting the B cell Maturation Antigen and its ligand, A Proliferation Inducing Ligand (BCMA-APRIL) in multiple myeloma.

Increasingly, there has been a lot of clinical interest in the BCMA target, but what about APRIL?

We spoke to one of the scientists involved in the research about this novel agent:

“It is very effective at abrogating the activity of APRIL and, in particular, in our models blocks the growth, survival, drug resistance, migration and adhesion of myeloma cells both in-vitro and in-vivo in our murine models. These models have been predictive for clinical activity of other novel targeted therapies including lenalidomide and bortezomib, and so we think targeting APRIL represents a very promising strategy.”

Sounds pretty good, right?

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Aloha! The Eddie Aikau Big Wave surf contest only happens on Waimea Bay on the North Shore of Oahu in a year when there are 40 ft swells. It’s six years since the last one took place.

Surfing Waimea Bay

Waimea Bay Surfing on Feb 10th 2016

Yesterday, at the last minute the big waves failed to show up as an expected storm took a different track.

In R&D terms this is a bit like a phase 3 trial that was expected to be positive, only at the last minute reads out negative.

Last year was an exceptional year in multiple myeloma with several new approvals. It was a “Grand Cru” year, but there is already another wave on the horizon…

Whether it’s a 40 foot Eddie Aikau wave remains to be seen, just like the bay and weather dictates the waves, clinical trial data and physician experience ultimately drive uptake.

This post continues our in-depth post-ASH analysis and pre-TANDEM coverage, with a look at the new wave in myeloma that’s coming our way.

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This year has been an unprecedented Grand Cru year for the field of multiple myeloma, with no less than four drugs approved by the FDA to date… the fourth one just this morning while writing this preview!

  • Panobinostat (Farydak) in relapsed/refractory disease in combination with bortexomib plus dexamethsone after at least 2 prior therapies.
  • Daratumumab (Darzalex) received accelerated approval based on phase 2 data and is human CD38-directed monoclonal antibody that is indicated for the treatment of patients who have received at least three prior lines of therapy.
  • Ixazomib (Ninlaro) is the first oral proteasome inhibitor and is approved in combination with lenalidomide plus dexamethasone, in people who have received at least one prior treatment.
  • Elotuzumab (Empliciti) is a monoclonal antibody against CS–1/SLAMF7 approved today in combination with lenalidomide plus dexamethasone after 1–3 lines of prior therapy.

There are also many promising new agents in development and quite a few that may well not make it to market as a result of newer, better tolerated agents coming through.

To learn more about our insights on multiple myeloma, subscribers can log in to read our latest ASH 2015 Preview.

Multiple myeloma (MM) has been very much in the news this week after the American Society of Clinical Oncology (ASCO) abstracts were released to much anticipation.

Myeloma is largely thought to be an incurable disease despite the option of an autologous stem cell transplant for newly diagnosed patients. That said, I have actually met some people who have had two or 3 transplants over several decades, a testament to their strength and fortitude in enduring such a challenging procedure.

This year, the news media have focused on elotuzumab (BMS/AbbVie), a CS1/SLAMF7 inhibitor that has previously shown clinical activity in earlier trials, after it was showcased in the ASCO Presscast last week. This why you see many articles on the data reported from this particular abstract.

New Orleans American QueenIt’s not the most exciting new data in this disease for me though, that honour goes to two other therapeutics of an entirely different kind. They come completely out of left field and what we saw over the last two months really caught our attention and may surprise you too.

Indeed, we saw hints of some of this data at the American Society for Gene and Cell Therapy (ASGCT) meeting last week in New Orleans.

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Coit Tower San FranciscoThe 2014 American Society of Hematology (ASH) annual meeting starts later this week in San Francisco. #ASH14 is a “must attend” given the innovation that has taken place in recent years for new treatments of blood related cancers.

One of the highlights of last year’s ASH was the data for CTL019 Chimeric Antigen Receptor CAR-T in children with acute lymphoblastic leukemia (ALL) presented by Stephan Grupp (CHOP). The data, in the opinion of many, was worthy of presentation in the plenary session of the meeting.

CAR-T cell therapy remains in the news, with the recent announcement that Seattle based Juno Therapeutics have an initial public offering (IPO) planned, and last week Kite Pharmaceuticals announced a secondary offering to raise additional funds. Last month, Houston based Bellicum Pharmaceuticals also filed an IPO to raise funds for development of their GvHD and CAR-T therapies.

It already looks a highly competitive marketplace and nobody is yet in phase 3 development. In addition to Juno, Kite, Novartis/UPenn and Bellicum, the Chinese also have CAR-T therapies in development. Other companies in the field include Cellectis, who have partnerships with Servier and Pfizer. On top of all this activity, only a week ago Janssen announced they had partnered with Transposagen Biopharmaceuticals. Wow!

In addition to ALL, CLL, and NHL, new developments are starting to emerge in myeloma, not just with CAR T cell therapies, but also checkpoint inhibitors and modified measles virus therapy.

Investor interest in immuno-oncology is certainly very high, and one has to question whether it is beginning to border on “tulip mania”? As we’ve written about on the blog, there remain a number of challenges that have to be overcome with CAR-T therapy, particularly in adults, and at the moment it’s still very much an experimental therapy.

In this post, we offer some top line thoughts on what to expect and look out for at ASH14 in Multiple Myeloma. It is consistently an area that attracts a lot of interest at the meeting and this year promises not to disappoint.

If you have to plans to be in San Francisco, do say “hello.”

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The big news yesterday evening was that Amgen’s phase III FOCUS trial in relapsed/refractory multiple myeloma failed to meet its primary endpoint of overall survival (HR=0.975).

Kyprolis logoSuch a marginal hazard ratio (HR) tells us that the risk of death was not reduced by taking carfilzomib over best supportive care.

According to the company:

“The 315-patient, open-label study evaluated single-agent Kyprolis® (carfilzomib) for Injection compared to an active control regimen of low-dose dexamethasone, or equivalent corticosteroids, plus optional cyclophosphamide in patients with relapsed and advanced refractory multiple myeloma. Nearly all patients in the control arm received cyclophosphamide. Patients were heavily pretreated and had received a median of five therapeutic regimens prior to study entry.”

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Recall the PANORAMA-1 trial for panobinostat with Velcade plus dex versus Velcade + dec alone was presented at ASCO and achieved positive PFS and OS. The patients in this study were refractory to 1-4 or 1-3 lines of prior therapy respectively, with nearly half (48.4%) receiving ≥ 2 prior therapeutic regimens. To put this in context, this was a much less heavily pretreated/refractory group overall than the FOCUS trial in comparison.

At ASCO, opinions from experts I spoke to regarding the likelihood of a successful result from FOCUS were evenly divided, while ASPIRE was widely expected to succeed. As one well respected European thought leader – who erred on the side of caution – pointed out to me:

“Low dose dex (with or without cyclophosphamide) is an active, but fairly low hurdle to beat, even for salvage therapy. In this situation, you do need a gentle, well tolerated regimen to stand a chance of a successful outcome. Carfilzomib is neither of those things, so no, I won’t be at all surprised if it fails.”

Add this latest finding to the results from the ASPIRE study last week, where the PFS was met and OS was not yet mature, makes for a very tricky time for Amgen should they wish to seek EU approval and reimbursement. It is likely that a solid positive result for OS from the ASPIRE study may well be necessary now for EU success.  If a therapy or regimen does not convincingly improve patient outcome, then it is unlikely to obtain reimbursement in Europe given the current economic environment.

The ASPIRE data alone may possibly be enough for confirmatory approval of carfilzomib in relapsed/refractory myeloma in the US because it was conducted under an SPA, but this is not a guarantee of success given other uncertainties surrounding the carfilzomib data and the secondary endpoint (OS).

What about adverse events?

Recall that with the ASPIRE data, the rate of cardiac events observed in the carfilzomib arm were consistent with the current label approved by FDA. Discussion on the rate of cardiac events have dogged the drug since accelerated approval by the FDA and the black box warning that accompanied the label.

However, in the FOCUS study an increase in the incidence of renal adverse events of all grades was observed in the carfilzomib arm compared to both the active control arm AND the label.

This is a new finding and of particular concern because myeloma patients do tend to experience more severe renal impairment with worsening disease, thus any therapy that hastens or worsens that situation is clearly not a good thing.

Overall

One thing is very clear from these recent data announcements – the mature ASPIRE data is now going to be very keenly watched at ASH this year. The Kaplan-Meier curves could well make or break the chances for Kyprolis in Europe and a miss on OS could possibly jeopardize the US confirmation, if the curves cross-over or do not have a compelling readout.

This week Amgen announced that their second generation proteasome inhibitor, carfilzomib (Kyprolis), had met the primary endpoint of progression free survival (PFS) in the phase III ASPIRE trial. This study compared the triple combination of Kyprolis plus Revlimid and low dose dexamethasone (KRd) to the doublet of Revlimid plus low dose dexamethasone (Rd) in relapsed/refractory multiple myeloma. The overall survival (OS) is not yet mature and statistical significance was not been reached at the interim analysis. We will have to see how that data is looking in a few months time at the American Society of Hematology (ASH) meeting in December.

This is an important trial because the data will enable Amgen to file for approval of carfilzomib in Europe with the survival data. The PFS for the two groups (26.3 vs. 17.6 months) showed a clear benefit in favour of adding carfilzomib to standard therapy by 8.7 months:

“Results from the ASPIRE study will form the basis for regulatory submissions through­out the world beginning in the first half of 2015.”

Allowing time for CHMP approval and country reimbursement, this means that carfilzomib will possibly be available in 1H16 in Europe.

What impact will this data have on the multiple myeloma landscape?

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The ASCO 2014 annual meeting starts on Friday in Chicago and there’s some interesting Multiple Myeloma (MM) data that we’ll be covering.

This preview outlines which MM data may be noteworthy at ASCO and for those going, I’ve included the session times and locations so you can mark your dance card accordingly. There will be more on the potential commercial implications of the data once they have been presented.

Although ASCO is mainly considered a solid tumour meeting, it has not been without some excellent data on hematologic malignancies over the years.

ASCO will always have a particularly soft spot for me since we launched imatinib (Gleevec) for advanced CML on the Friday of ASCO way back in 2001. Many readers may know that I was in new products at Novartis Oncology and was heavily involved in bringing STI571, as it was originally known, to market and subsequently moved on to the brand team.

Gleevec on cover of Time MagazineThe meeting happened in a blur; on Friday we shipped drug for the first scripts the same day within hours of approval received that morning, flew to the conference, had a packed hall with standing room only for 2,000 people in a CME session in the afternoon, presented the one-year phase 3 IRIS data on the Monday, and received a very nice mention from Dr David Scheinberg (MSK), one of the phase 2 trialists during the Sunday plenary session. All these events occurred only a few days after hitting the front page of TIME magazine. It took quite a few weeks to come down from that incredible high!

When people insist ASCO is a solid tumour meeting, I always smile and remember that isn’t always the case.

Hematologic malignancies can generate excellent data mid year. This year, there is good news to discuss, not in CML, but multiple myeloma (MM) at both ASCO and at the European Hematology Association (EHA) Congress in Milan from June 12-15. There is also some nice CLL data, which I will cover in a separate preview.

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In today’s post, we discuss multiple myeloma and the proteasome inhibitors (bortezomib, carfilzomib and ixazomib), in particular. One of the ongoing debates concerns the toxicities and how the drugs in this class might differ. Whereas melphalan and the immunomodulatory drugs or IMiDs (lenalidomide, pomalidomide and thalidomide) have both been associated with secondary primary malignancies including AML and MDS, especially in combination, cardiotoxicity has been the main focus of debate for the proteasome inhibitors.

Is this a fair rap though?

We should remember that people with multiple myeloma typically tend to be around age 70. Think of Tom Brokaw, the famous newscaster, who was recently diagnosed with the condition aged 74 and is in the median age range, for example. In general, most people over 65 tend to have an increased incidence of cardiovascular disease and myeloma patients also tend to have a slightly higher risk due to disease factors, so there is a background effect that needs to be taken into account.

We should be mindful of the recent scare with cardiovascular events associated with ponatinib (Iclusig) in relapsed/refractory CML, which led to a temporary suspension from the US market and subsequent re-instation with a narrower license, appeared to unnerve both the FDA and investors alike.

At the American Society of Hematology (ASH) meeting in Decemeber, there were some interesting posters, presentations and debates on the proteasome inhibitors in myeloma that are worthy of further discussion. In addition, I sought some thought leader opinions and curated some of the interactions on this topic to add some colour commentary.

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