By Jack Aiello
San Francisco/Greater Bay Area, CA
@JackMAiello
[email protected]

December 8, 2014 was the final full day of the 56th American Society of Hematology (ASH) Annual Meeting. I’ve been asked to name one to two of ASH’s blockbusters for multiple myeloma treatment, but I don’t think there were any this year– at least in terms of previously unannounced new treatments that patients should consider trying. However, many of the 855 poster presentations are identifying potential myeloma therapy targets for which a drug needs to be developed or an existing drug tried. So who knows, perhaps one of the targets/drugs will be a future blockbuster.

I attended oral presentations in the morning beginning at 7 am, and the first presentation examined a pan-PIM kinase (think “target”) inhibited by a new oral drug called LGH447. This phase I trial of relapsed/refractory (r/r) patients showed single-agent ORR (overall response rate) of 10.5% (best response was VGPR (very good partial response)) over all doses 70 – 700 mg and decided on a best dose of 500 mg for future trials.

Trial results for the monoclonal antibody (mAb) elotuzumab were first announced three to four years ago. Today a phase II trial for elotuzumab (10 mg/kg) plus Revlimid (lenalidomide)-dexamethasone for R/R (but Rev-naive) patients showed 92% ORR (43% >= VGPR) and median PFS (progression-free survival) of 32 months. By the way, this was previously described as a CS-1 mAB but now is called a SLAMF7 (formerly CS-1) mAb, which is expressed on 95% of myeloma cells but very little on normal tissue.

Pomalyst (Pomalidomide)/Cytoxan/dexamethasone (PCd) was also tested in a phase II trial for R/R patients who were 100% refractory to Revlimid, 75% refractory to Velcade (bortezomib) and 40% refractory to Kyprolis (carfilzomib)… So these 36 patients were running out of options. Yet, with ORR of 65% and PFS of nine and a half months and median OS (overall survival) not yet reached after approximately two years, this combination appears to be very beneficial. Interestingly though, for those others in a Pomalyst/dexamethasone arm, adding Cytoxan to their regimen did not improve their responses, which were all lower than the PCd arm.

For another set of similar R/R patients, Velcade was added to Pomalyst/dexamethasone and showed ORR 85% (>= VGPR 45%), including an ORR of 82% in high-risk patients. Median PFS overall was 10.7 months (16.3 standard risk, 9.5 high risk), so this also appears to be another effective option.

Some interesting posters:

* Giving Velcade after relapsing from an allo transplant resulted in 58% ORR and 7 months median PFS. While a previous study showed Revlimid numbers to be higher at 83% and 18 months respectively, Revlimid resulted in acute graft-versus-host disease (GVHD), while Velcade had no impact on GVHD.
* A third auto SCT at late MM relapse resulted in 6 months PFS and 30 months OS.
* Poster 3994 indicated that Revlimid and Velcade are still not particularly helpful for the high-risk factor 17p deletion.
* BT062 is a combination mAb targeting CD138 with an agent called DM4 release to kill the cancer cell. When BT062 is given with Revlimid/dexamethasone to R/R patients already exposed to Revlimid and Velcade, this phase I/IIa study defined MTD (maximum tolerated dose) of 100mg/m2 and resulted of ORR of over 70% including for those refractory to Revlimid.

Later, the IMF hosted the International Myeloma Working Group (IMWG) Conference Series: Making Sense of Treatment, featuring Drs. Brian Durie (IMF), Ola Landgren (Memorial Sloan Kettering), Joseph Mikhael (Mayo Clinic), and Antonio Palumbo (University of Torino). Here are some of their thoughts, but you should go to the IMF website (http://bit.ly/1qvkcdq) and listen to a replay yourself (especially because my watching live streaming via Wi-Fi disconnected a few times so I’ll watch again):

BD: 855 MM abstracts, with about 130 key ones including 24 oral presentations.

* High Risk Smoldering MM. Revlimid/dexamethasone has OS benefit five years out. Kyprolis/Revlimid/dexamethasone excellent responses. Ultra High Risk (plasma > 60%, free light-chain ratio > 100, or MRI focal lesions > 1) is now considered MM. But we don’t know exactly who in high risk group should be in “ultra” high risk until clinical trials yield results. Current treatment strategy for high risk SMM? Palumbo said: More intense therapy than Revlimid only; Mikhael agreed with Palumbo; Landgren: Kyprolis/Revlimid/dexamethasone is his trial which resulted in most of his 12 patients reaching MRD-negative status.
* Front-line therapy for Transplant Eligible. Landgren: Revlimid/Velcade/dexamethasone (RVd) for all patients independent of risk, but given ASPIRE data, KRd (Kyprolis/Revlimid/dexamethasone) is reasonable. Mikhael agreed with Landgren; Palumbo: RVd or Velcade/Cytoxan/dexamethasone (VCd), but Kryprolis appears superior.
* Front-line therapy for Transplant Non-Eligible. Palumbo: Fit – RVd or VCd; Unfit – Rd or Vd. Mikhael: Similar to Palumbo but [lost connection].
* Minimal Residual Disease (MRD): Depth of MRD correlates to PFS and OS. Landgren: We should not PUSH to MRD at any price. Mikhael pretty much agreed with Landgren but a bit more aggressive for high risk patients. However, lots of further study needs to be done to understand the impact of MRD numbers.
* Role of Transplant [Lost connection during this part of the discussion.] Palumbo: “Today we do not have a drug that outweighs the benefit of early transplant.” Landgren: Patients are certainly asking the question to transplant or not. Studies are being done. Mikhael: We shouldn’t be bound by number of cycles (typically four) before transplant.
* Maintenance: Continuous versus Fixed? Mikhael: Field moving toward continuous therapy. Definitely for high-risk, although maybe more consolidation. For standard risk, some patients (but we don’t know who) will do fine without maintenance. Palumbo: Continuous treatment has shown benefit so this makes sense provided minimal toxicities. Trial with ixazomib maintenance showed 50% of patient responses improved. Landgren: Continuous but exact or best answer is unknown.
* Best Imaging Techniques. Palumbo: low-dose CT scan should be first level of testing, then whole-body MRI, some skepticism with PET due to false positives. Landgren: MRI best technology for imaging bone marrow but CT/PET is best for imaging bone. Mikhael: For smoldering looks hard for evidence so might do MRI and CT/PET. For MM, start with skeletal survey, and move sequentially forward through other techniques if necessary.
* Relapse/Which Novel therapies are most promising. Palumbo: mAbs. He hopes HDAC inhibitors will be improved. Mikhael: CD38 mAbs. Oprozomib showed single-agent activity in Kyprolis-refractory patients. Landgren: CD38 mAbs. CAR-T cells need to be explored.

Well that’s it for December 8th. I’ll be blogging a summary as well as creating a Word file with details of trial results that I found interesting. Just email me [email protected] if you want a copy.

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