May 28, 2020

Virtual ASCO

This weekend, researchers would have been descending on Chicago for the 56th Annual Meeting of the American Society of Clinical Oncology (ASCO) (https://www.asco.org/meetings) to learn the latest about myeloma research, along with thousands of other subspecialty cancer investigators. Now, due to the coronavirus pandemic, we await the Zoom discussions and Twitter feeds to learn what was important.

Most abstracts have already been posted online (https://s3.amazonaws.com/files.oncologymeetings.org/prod/s3fs-public/2020-05/AM20-HEMATOLOGIC-MALIGNANCIES%E2%80%94PLASMA-CELL-DYSCRASIA.pdf?null) and we are learning that some slides will be available on Friday, the opening day of the three-day meeting (May 29-31). Patient advocates who registered in advance for this Virtual ASCO meeting can access the live-streamed presentation and discussion periods for both oral and poster presentations.

In the meantime, here is what to look out for from among the over 2,000 ASCO abstracts:

Top Myeloma Oral Presentations

The top myeloma presentation for ASCO 2020 is LBA-3 (https://meetinglibrary.asco.org/record/186906/abstract), a late-breaking abstract presented by Dr. Shaji Kumar, which presents for the first time the results comparing the combination of Kyprolis + Revlimid + dexamethasone (KRd) versus Velcade + Revlimid + dexamethasone (VRd) in the frontline setting. 

The other major oral presentations at ASCO provide updates and confirmation of results and benefits with several immune therapies (CAR T-cell; belantamab mafodotin; teclistamab and CELMoD), as well as follow-up on some key trials, including the STaMINA transplant trial, the BELLINI trial with venetoclax, the BOSTON trial with selinexor, and the SWOG trial evaluating elotuzumab in high-risk myeloma.

Key Points

• Late-breaking abstract 3 (https://meetinglibrary.asco.org/record/186906/abstract): Results of this pivotal trial (ENDURANCE), which compares KRd to VRd in newly diagnosed multiple myeloma (NDMM), are the most anticipated new myeloma findings to be reported at ASCO 2020. The important question is whether or not substituting Kyprolis (K) for Velcade (V) in the frontline combination will provide added benefit with acceptable toxicity. In this randomized phase III trial, KRd did not improve PFS compared with VRd in NDMM. A significantly higher rate of cardio-pulmonary and renal toxicity was observed with KRd, while neuropathy rates were higher with VRd. VRd remains the standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4-drug combinations.
• CAR T-cell therapies 
  • Ide-cel, bb2121 anti-BCMA CAR-T cell product (abstract #8503 (https://meetinglibrary.asco.org/record/186139/abstract)) results will be presented by Dr. Nikhil Munshi for the 140 patents enrolled in the KarMMa* trial for patients with relapsed and refractory disease who have received 3 or more prior regimens. Deep, durable responses are again confirmed in this very heavily previously treated patient group. The cytokine release (CRS) side effects were manageable. By tripling the CAR T-cell dosage from 150 million to 450 million, the overall response rate (ORR) and depth of response increased from 50% ORR to 82% ORR, and median PFS (progression-free survival) increased up to 11.8 months. This therapy is currently under review at the FDA with a decision expected by year’s end. Clinical trial results using another CAR T-cell product (orva-cel, a Juno/Bristol Myers Squibb collaboration) will also be presented, with promising early results (abstract # 8504 (https://meetinglibrary.asco.org/record/186159/abstract)). *Additional KarMMa data in the “real world” setting are presented in abstract #8525 (https://meetinglibrary.asco.org/record/186190/abstract).
  • JNJ-4528 CAR T-cell product (abstract #8505 (https://meetinglibrary.asco.org/record/186155/abstract)) results will be presented by Dr. Jesus Berdeja for the patients treated in this CARTITUDE-1 trial for relapsed and refractory patients who have undergone three or more prior lines of therapy. As noted at the 2019 ASH (the American Society of Hematology) Annual Meeting (https://www.myeloma.org/ash-2019/results-cartitude-1-phase-1b2-study-jnj-4528-car-t-cell-therapy-directed-against-b-cell), 100% of patients responded, with 76% having deep responses (stringent CR) and manageable CRS toxicities. These data will be submitted for FDA review in the coming months.
• Monoclonal antibody/drug conjugate belantamab mafodotin (Bela), an anti-BCMA product. Results of the DREAMM-6 trial (abstract #8502 (https://meetinglibrary.asco.org/record/186921/abstract)), which combines Bela with bortezomib and dexamethasone, will be presented by Dr. Ajay Nooka. Early results are encouraging, with an acceptable safety profile. Other DREAMM trial data to be presented at ASCO: abstract #8519 (https://meetinglibrary.asco.org/record/187591/abstract)(renal impairment); abstract #8536 (https://meetinglibrary.asco.org/record/186180/abstract) (DREAMM-2); abstract #8541 (https://meetinglibrary.asco.org/record/187531/abstract) (looking at high-risk myeloma cytogenetics); TPS8552 (https://meetinglibrary.asco.org/record/191912/abstract) (DREAMM-5); and TPS8556 (https://meetinglibrary.asco.org/record/191729/abstract) (DREAMM-9, Bela combined with VRd).


• Other novel/immune-therapy approaches to be presented at ASCO 2020 include the trial with teclistamab, a novel bi-specific monoclonal antibody linking BCMA and CD3 T cells (abstract #100 (https://meetinglibrary.asco.org/record/186864/abstract), presented by Dr. Saad Usmani) and the trial with CC-92480, a cereblon E3 ligase modulator (CELMoD), (abstract #8500 (https://meetinglibrary.asco.org/record/186136/abstract), presented by Dr. Paul Richardson). Both trials show early promising results in refractory patients, with acceptable toxicity profiles. Data with isatuximab will also be presented (abstract #8508 (https://meetinglibrary.asco.org/record/186909/abstract)) evaluating the combination with KRd in the frontline setting. A helpful study (abstract #8526 (https://meetinglibrary.asco.org/record/186186/abstract)) compares twice-weekly Kyprolis with weekly Kyprolis,  illustrating the efficacy and safety with the once-per-week schedule.

Additional Notable Trial Results

• The STaMINA trial update (abstract # 8506 (https://meetinglibrary.asco.org/record/186147/abstract), presented by Dr. Parameswaran Hari) presents a long-term follow-up of this evaluation of autologous stem-cell transplant (ASCT). Using ITT (intent to treat) analysis outcomes for the three arms of the trial were, as in the past, not different. However, looking at the outcomes related to the treatment actually administered, there was a PFS benefit for patients receiving tandem (double) ASCTs, mostly reflecting benefit for patients with high-risk disease. Although this remains a controversial conclusion, the benefit in high-risk disease is supported by other European trial data.
• The SWOG high-risk multiple myeloma trial (abstract #8507 (https://meetinglibrary.asco.org/record/186157/abstract), presented by Dr. Saad Usmani) evaluates Velcade + Revlimid + dexamethasone, with and without elotuzumab. There was, unfortunately, no added benefit with the addition of elotuzumab, but this study serves as a key benchmark for future trials in this setting.
• The BOSTON trial results (abstract #8501 (https://meetinglibrary.asco.org/record/186143/abstract), presented by Dr. Meletios Dimopoulos) evaluates Velcade + dexamethasone, with and without selinexor. This trial confirms prior reports indicating significant added benefit with selinexor and manageable toxicity. This is encouraging news for the use of selinexor combinations in the clinic.
• The BELLINI trial results (abstract #8509 (https://meetinglibrary.asco.org/record/186148/abstract); Dr. Shaji Kumar: poster discussion) again evaluate the impact of adding venetoclax (a selective anti-BCL2 agent) to the combination of Velcade +  dexamethasone. As first reported, there is continued benefit only for patients with t[11;14] disease, with an unfortunate negative impact on outcomes for other patients, including increased treatment-emergent deaths. This has led to an appropriate focus on t[11;14] disease for this exciting new agent, which does induce deep and beneficial response for this patient subset. Additional venetoclax data are presented in abstracts #8511 (https://meetinglibrary.asco.org/record/187561/abstract) and #8547 (https://meetinglibrary.asco.org/record/186191/abstract).

Interesting Poster Presentations

In addition to the oral presentations, several ASCO 2020 posters provide interesting new information: 

• The CASSIOPEIA trial results (abstract #8538 (https://meetinglibrary.asco.org/record/187699/abstract): Dr. Cyrille Touzeau) are updated to evaluate the impact of earlier disease. Looking at patients with so-called “SLiM-CRAB,” those patients meeting the new criteria based upon biomarkers, it is important to note that the four-drug combination of daratumumab + VTd (versus VTd alone) is especially effective used in the early disease setting, with a 97% ORR and 67% MRD negative (at 10 to -5 level). This was statistically superior to results for CRAB-positive patients and reinforces the notion that early aggressive treatment is a valid approach in achieving best outcomes. 
• Three abstracts assessing MRD (minimal residual disease) testing:
  • In abstract #8512 (https://meetinglibrary.asco.org/record/186156/abstract) (Dr. Noemi Puig), the results of mass spectrometry (Mass Spec) testing of serum were again compared with NGF (next-generation flow cytometry) MRD test results for patients in the CESAR HR SMM trial (a Black Swan Initiative Cure Trial (https://www.myeloma.org/black-swan-research-initiative/black-swan-research-projects)), which has a very high MRD-negative rate. The bottom line is that for some patients who remain positive with Mass Spec, this predicts for relapse even with NGF negative results. It seems that for the future, these two tests can be used in a complementary fashion to fine-tune disease monitoring and achieve the best outcomes.
  • A similar conclusion is reached in abstract #8513 (https://meetinglibrary.asco.org/record/186146/abstract) (Dr. Benjamin Derman) in comparison to NGS (next-generation sequencing) MRD testing. There is helpful information from the positive Mass Spec results regarding likely impending relapse. 
  • A related abstract (#8514 (https://meetinglibrary.asco.org/record/186150/abstract): Dr. Meera Mohan) also notes that careful ongoing disease-monitoring is required because within the first 5 years as many as 40% of patients can switch back to MRD-positive from MRD-negative and NOT retain a sustained MRD-negative status. This is all very helpful information to guide expectations and decision-making.

And the Real Pandemic

Amid all this great news about new therapies and options, it is important to remain alert about the impact of the ongoing COVID-19 crisis. As we attempt to mourn the loss of over 100,00 lives in the U.S., we are faced with the reality of continued virus spread in the community. This is a particular concern for myeloma patients attempting to achieve a new normal.

The uncertainties about testing, vaccine development and treatments for COVID-19 mean that distancing measures, masks and careful hand-washing remain the mainstays of prevention. Coordinated efforts in places like New Zealand (https://www.npr.org/sections/goatsandsoda/2020/05/23/861577367/messaging-from-leaders-who-have-tamed-their-countrys-coronavirus-outbreaks) illustrate what can be accomplished with collaboration, compassion and kindness — the central theme of the Prime Minister’s efforts to contain COVID-19. With simple common sense we can indeed get through these crazy times together and re-open our communities.