Myeloma Canada’s Top 3 Takeaways from ASH 2017

Every December, thousands of hematologists from across the world convene for the American Society of Hematology (ASH) Annual Meeting. This past month, from approximately 5,000 scientific abstracts presented at ASH, the latest ground-breaking clinical research in myeloma was showcased.

Adding Daratumumab (Darzalex®) to Either Lenalidomide (Revlimid®) or Bortezomib (Velcade®) and Dexamethasone in Relapsed or Refractory Myeloma Patients Delays Disease Progression: POLLUX and CASTOR Trial Updates

Lenalidomide (Revlimid®) or bortezomib (Velcade®) along with dexamethasone are two widely used standards of care treatment regimens (Rd and Vd, respectively) for patients with relapsed or refractory myeloma. Updated data from two open-label phase III trials, POLLUX ( NCT02076009 ) and CASTOR ( NCT02136134 ), demonstrated that adding daratumumab (Darzalex®) to either regimen improves progression-free survival (PFS) in this patient population. Overall survival has not yet been reported for both trials.

Daratumumab is a human monoclonal antibody (IgGκ) that targets and binds to a protein, CD38, which is overexpressed on the surface of myeloma cells. When daratumumab binds to CD38, it triggers cytotoxicity inside myeloma cells and causes apoptosis (cell death). The drug also helps a person’s immune system attack other myeloma cells through various mechanisms of action and effects (immunomodulatory or immune-mediated).

POLLUX (DRd versus Rd)

Of the 569 patients being followed, approximately half were randomly assigned to either regimen/arm (DRd = 286; Rd = 283). The median duration of treatment was reported to be 30.4 months for the DRd arm and 16 months for Rd arm. PFS at 30 months was 73% (median PFS not reached) and 58% (median PFS = 32.3 months) in both arms, respectively. Furthermore, the results showed that the DRd group achieved minimal residual disease (MRD) negativity more rapidly and it improved over time. MRD negativity in the Rd group climbed slowly and plateaued quicker. Regarding safety, no differences were observed in treatment discontinuation due to adverse events; however, 39% of patients in the DRd arm experienced grade 3 or 4 infections (versus 26% in the other arm).

Data from the DRd group had not yet yielded a median time to next therapy; however the median time to next therapy was reported to be 22.3 months in the Rd arm. Of the patients from the DRd arm that continued to their next treatment, a prolonged secondary PFS (PFS2) was observed, suggesting that DRd provides a clear clinical benefit without negatively impacting subsequent therapies.

CASTOR (DVd versus Vd)

Median PFS at 24 months was not reached in the DVd arm of the CASTOR trial, compared to 20.7 months in the Vd arm. Subgroup analyses found that patients with one prior line of therapy (including those who were treated with bortezomib and lenalidomide-refractory patients) as well as those who had high cytogenetic risk, all benefitted from the treatment. Finally, responses remained durable in patients who received daratumumab monotherapy as maintenance therapy.

STOMP (MCRN 002) Trial Update

The STOMP ( MCRN 002 ; NCT02343042 ) is a Phase I/II trial that is evaluating selinexor (KPT-330), along with dexamethasone, in combination with various "backbone" therapies (either bortezomib [Velcade®], lenalidomide [Revlimid®], pomalidomide [Pomalyst®] and daratumumab [Darzalex®]) in patients who received one or more prior therapies, including those who had prior exposure or were refractory to a proteasome inhibitor. Patients who were refractory to bortezomib as their last therapy were not eligible for the bortezomib arm of the trial.

Selinexor is an oral drug that works by binding with and inhibiting a nuclear export protein XPO1 (also called CRM1), resulting in the accumulation of tumour suppressor protein inside cells. This leads to the reinitiation (and amplification) of the cell’s ability to suppress tumours, possibly by stimulating selective cell death (apoptosis) in cancer (myeloma) cells, generally sparing normal cells. When given along with a steroid (ie, dexamethasone), selinexor has been shown to increase the clinically beneficial effects of steroids through effects inside the cell.

Selinexor combined with weekly low-dose bortezomib and low-dose dexamethasone (SVd) induces a high response rate with durable responses in patients with refractory myeloma

As of July 15, 2017, a total of 42 patients were enrolled in the SVd cohort of the study with 40 patients evaluated for response. Results showed an overall response rate of 83%, specifically 84% of the proteasome inhibitor (PI)-naïve or PI-relapsed patients. Forty-three percent (43%) of the PI-refractory patients responded, supporting preclinical evidence that selinexor can resensitize resistance to PIs. The majority of patients that responded demonstrated a drop in M-protein, with 33% achieving a 90% or greater drop. The median progression-free survival (PFS) was 9 months. Median PFS in PI-naïve or relapsed patients was reported to be greater than 13 months.

Among the responders, the median time to response was 1.1 months, with a median duration of approximately 12 months. Adverse events were consistent with those previously reported for this arm of the study; however peripheral neuropathy was limited to a total of six patients (14%), five of whom had prior exposure to bortezomib.

The all-oral combination of selinexor, pomalidomide and low-dose dexamethasone (SPd) is a safe and well-tolerated regimen with significant clinical activity in patients with relapsed and refractory myeloma

As of July 15, 2017, a total of 29 patients were enrolled in the SPd arm of the STOMP study with 24 patients evaluated for response. Updated results from this all-oral regimen showed that one-weekly dose of selinexor can be safely combined with Pd. An overall response rate of 54% and a median progression-free survival (PFS) of 11.6 months was reported in myeloma patients whose disease is refractory to a proteasome inhibitor (PI; eg, bortezomib) and an immunomodulatory drug (IMiD; eg, lenalidomide, pomalidomide). Pd is an approved standard of care regimen for myeloma patients who are refractory to a PI and an IMiD. Previous results have shown that the Pd regimen in the same patient population has an overall response rate of approximately 30% and PFS of approximately four months. Compared to selinexor or Pd alone, no additional toxicity was observed.

This reported increase in overall response rate and PFS continues to support evidence that the all-oral SPd regimen is being generally well tolerated and rapidly induces durable responses in patients that are refractory to a PI and an IMiD (including pomalidomide).

The all-oral combination of selinexor, lenalidomide and low-dose dexamethasone (SRd) is a safe regimen with a high response rate in patients with relapsed and refractory myeloma

As of July 15, 2017, a total of 18 patients were enrolled in the SRd arm of the STOMP study with 15 patients evaluated for response. This cohort is evaluating patients who received at least one prior therapy, including prior lenalidomide unless the patient’s myeloma was refractory to it. Conversely, patients who were refractory to lenalidomide maintenance were included in this arm.

Updated results reported an overall response rate of 73%, including 91% among patients who had not previously received lenalidomide (11 patients). The median progression-free survival (PFS) was not yet reached for the entire patient population or for those who were lenalidomide-naïve. The median PFS reported in the lenalidomide refractory/relapsed patients was 6.6 months. Regarding safety, no new or unexpected cardiac, pulmonary, liver or renal toxicity was observed. These results demonstrate that the all-oral SRd regimen is safe and has a high response rate, especially in lenalidomide-naïve myeloma patients with relapsed and refractory disease.

Early results show that selinexor combined with daratumumab and low-dose dexamethasone (SDd) is a promising regimen in patients with relapsed

and refractory myeloma

As of July 15, 2017, a total of 6 patients were enrolled in the SDd cohort of the STOMP trial. This study is evaluating myeloma patients who received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), or patients with disease refractory to both a PI and an IMiD. Patient either received 100mg oral selinexor (once weekly) or 60mg (twice weekly) along with intravenous daratumumab (16mg/kg; once weekly) and 40mg oral dexamethasone (once weekly or 20mg twice weekly). Preliminary tolerability and efficacy data suggest a recommended Phase II dose of 100mg oral selinexor (once- weekly). All (three) patients in the 100mg oral selinexor group had a partial response (2 unconfirmed) after the first treatment cycle and remained part of the study.

Regarding safety, the most common Grade 1/2 adverse events were fatigue, nausea, and neutropenia. The most common Grade 3/4 adverse events were thrombocytopenia, leukopenia, anemia and neutropenia.

Overall, these early study results suggest that SDd is a promising regimen in patients who received at least three prior lines of therapy. Study enrollment is ongoing and full Phase I data will be updated and presented.

BCMA CAR T-cell Therapy Continues to Look Promising in Patients with Heavily Pre-treated Relapsed and

Refractory Myeloma

Previous results from an ongoing multicentre Phase I B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell study ( NCT02658929 ) showed promising results with 100% of the evaluated patients in active dose arms (above 50 x 10 ⁶ CAR T-cells) achieving an objective response and no disease progression as of May 4, 2017.

T-cells are types of white blood cells that migrate to, and form in the thymus gland of the neck. They play essential roles in the immune system function by acting like soldiers who find and destroy targeted invaders (antigens) throughout the body. CAR T-cell therapy works by collecting T-cells from the blood of patients and genetically engineering them to produce special receptors (CARs) on their surface that recognize the specific protein (antigen) that is highly produced by their cancer cells (ie, BCMA in myeloma cells). The engineered CAR T-cells are then grown in the laboratory and injected back into the patient to fight their cancer cells.

The study examined a variety of doses ranging from 50 to 300 × 10 ⁶ CAR T-cells, with the lowest dose (50 x 10 ⁶ ) not showing clinical activity. Updated results from this trial suggest durable clinical responses for doses above 50 x 10 ⁶ CAR T-cells.

A total of 21 patients have been enrolled in the trial, with 18 patients evaluated for initial response (median time to first response was 1.02 months). The median time to best response was 3.74 months and the median time to complete response 3.84 months.

The reported overall response rate was 94% in patients who received a dose of 150 x 10 ⁶ CAR T-cells or higher, with 89% and 56% of patients achieving a very good partial response or better or a complete response or better, respectively.

At the median follow-up of 40 weeks, nine out of ten patients evaluated for minimal residual disease (MRD) were MRD negative, median progression-free survival (PFS) had not yet been reached and the 9-month PFS rate was reported as being 71%.

Regarding safety, 14 (of 21) patients experienced at least 1 serious adverse event; however they were reported to be manageable with some (grade 3) resolving within 24 hours. There have been a total of 5 deaths in the trial (3 from disease progression; 1 from cardiac arrest; 1 from myelodysplastic syndrome following treatment discontinuation).

Overall these updated results are very encouraging as the patients enrolled had a median of seven prior therapies (all had an autologous stem cell transplant) and a median of five years since diagnosis. Moreover, 29% of patients were refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab and 43% of patients had high-risk disease (cytogenetics). The global Phase II KarMMa trial ( NCT03361748 ) is open for enrollment and plans on enrolling 94 patients with relapsed/refractory myeloma.